U.S. patent application number 10/336344 was filed with the patent office on 2003-07-10 for aryl or heteroaryl substituted 3,4-dihydroanthracene and aryl or heteroaryl substituted benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3- -ene and benzo [1,2-g]-1,2-dihydroquinoline derivatives having retinoid antagonist or retinoid inverse agonist type biological activity.
Invention is credited to Chandraratna, Roshantha A., Johnson, Alan T., Vuligonda, Vidyasagar.
Application Number | 20030130515 10/336344 |
Document ID | / |
Family ID | 25070815 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030130515 |
Kind Code |
A1 |
Vuligonda, Vidyasagar ; et
al. |
July 10, 2003 |
Aryl or heteroaryl substituted 3,4-dihydroanthracene and aryl or
heteroaryl substituted benzo[1,2-g]-chrom-3-ene,
benzo[1,2-g]-thiochrom-3- -ene and benzo
[1,2-g]-1,2-dihydroquinoline derivatives having retinoid antagonist
or retinoid inverse agonist type biological activity
Abstract
Compounds of the formula 1 where the symbols have the meaning
defined in the specification, have retinoid, retinoid antagonist
and/or retinoid inverse-agonist-like biological activity.
Inventors: |
Vuligonda, Vidyasagar;
(Irvine, CA) ; Johnson, Alan T.; (Rancho Santa
Margarita, CA) ; Chandraratna, Roshantha A.; (Mission
Viejo, CA) |
Correspondence
Address: |
Brent A. Johnson
Allergan, Inc.-T2-7H
2525 Dupont Drive
Irvine
CA
92612
US
|
Family ID: |
25070815 |
Appl. No.: |
10/336344 |
Filed: |
January 2, 2003 |
Related U.S. Patent Documents
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10336344 |
Jan 2, 2003 |
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09482700 |
Jan 13, 2000 |
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6538149 |
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09482700 |
Jan 13, 2000 |
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09030350 |
Feb 25, 1998 |
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6087505 |
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09030350 |
Feb 25, 1998 |
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08764466 |
Dec 12, 1996 |
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5728846 |
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Current U.S.
Class: |
546/14 ;
546/280.1; 546/282.7; 546/285; 548/181; 549/26; 549/356; 549/385;
549/60; 558/414; 560/34 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 213/55 20130101; C07D 311/92 20130101; C07D 333/24 20130101;
A61P 17/00 20180101; A61P 25/28 20180101; C07C 69/76 20130101; A61P
35/00 20180101; C07D 335/08 20130101; A61P 1/00 20180101; C07C
45/00 20130101; A61P 43/00 20180101; A61P 31/12 20180101; A61P 3/06
20180101; C07C 2603/24 20170501; A61P 27/00 20180101; C07D 409/06
20130101; A61P 9/00 20180101; C07C 47/548 20130101; A61P 37/00
20180101; C07C 45/00 20130101; C07C 47/548 20130101 |
Class at
Publication: |
546/14 ;
546/280.1; 546/282.7; 546/285; 548/181; 549/26; 549/60; 549/385;
549/356; 558/414; 560/34 |
International
Class: |
C07F 007/02; C07D
335/08; C07D 417/02; C07D 45/02; C07D 49/02 |
Claims
What is claimed is:
1. A compound of the formula 12wherein X.sub.1 is
--C(R.sub.1).sub.2--, --C(R.sub.1).sub.2--C(R.sub.1).sub.2--,
--S--, --O--, --NR.sub.1--, --C(R.sub.1).sub.2--O--,
--C(R.sub.1).sub.2--S--, or --C(R.sub.1).sub.2--NR.sub.1--; R.sub.1
is independently H or alkyl of 1 to 6 carbons; R.sub.2 is optional
and is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I,
CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH,
alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; m is an
integer between 0 and 4; n is an integer between 0 and 2; o is an
integer between 0 and 3; R.sub.3 is hydrogen, lower alkyl of 1 to 6
carbons, F, Cl, Br or I; R.sub.4 is (R.sub.5).sub.p-phenyl,
(R.sub.5).sub.p-naphthyl, or (R.sub.5).sub.p-heteroaryl where the
heteroaryl group is 5-membered or 6-membered and has 1 to 3
heteroatoms selected from the group consisting of O, S and N; p is
an integer having the values of 0-5; R.sub.5 is optional and is
defined as independently F, Cl, Br, I, NO.sub.2, N(R.sub.8).sub.2,
N(R.sub.8)COR.sub.8, NR.sub.8CON(R.sub.8).sub.2, OH, OCOR.sub.8,
OR.sub.8, CN, COOH, COOR.sub.8 an alkyl group having 1 to 10
carbons, fluoro substituted alkyl group having 1 to 10 carbons, an
alkenyl group having 1 to 10 carbons and 1 to 3 double bonds,
alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a
(trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups
independently have 1 to 6 carbons; Y is a phenyl or naphthyl group,
or heteroaryl selected from a group consisting of pyridyl, thienyl,
furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,
imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl
groups being optionally substituted with one or two R.sub.2 groups,
or Y is --(CR.sub.3.dbd.CR.sub.3).sub.r--; r is an integer between
1 and 3; A is (CH.sub.2).sub.q where q is 0-5, lower branched chain
alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl
having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6
carbons and 1 or 2 triple bonds, with the proviso that when Y is
--(CR.sub.3.dbd.CR.sub.3).sub.r-- then A is (CH.sub.2).sub.q and q
is 0; B is hydrogen, COOH or a pharmaceutically acceptable salt
thereof, COOR.sub.8, CONR.sub.9R.sub.10, --CH.sub.2OH,
CH.sub.2OR.sub.11, CH.sub.2OCOR.sub.11, CHO, CH(OR.sub.12).sub.2,
CHOR.sub.13O, --COR.sub.7, CR.sub.7(OR.sub.12).sub.2,
CR.sub.7OR.sub.13O, or Si(C.sub.1-6alkyl).sub.3, where R.sub.7 is
an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
R.sub.8 is an alkyl group of 1 to 10 carbons or
(trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or
a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or
lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen,
an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10
carbons, or phenyl or lower alkylphenyl, R.sub.11 is lower alkyl,
phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13
is divalent alkyl radical of 2-5 carbons.
2. A compound of claim 1 where Y is phenyl or naphthyl.
3. A compound of claim 1 where Y is selected from pyridyl, furyl
and thienyl.
4. A compound of claim 1 where Y is
--(CR.sub.3.dbd.CR.sub.3).sub.r--.
5. A compound of claim 1 where X.sub.1 is
--C(R.sub.1).sub.2--C(R.sub.1).s- ub.2--.
6. A compound of claim 1 where X.sub.1 is
--C(R.sub.1).sub.2--O--.
7. A compound of claim 1 where X.sub.1 is
--C(R.sub.1).sub.2--S--.
8. A compound of claim 1 where X.sub.1 is
--C(R.sub.1).sub.2--N--.
9. A compound of claim 1 where A is (CH.sub.2).sub.q and B is COOH
or a pharmaceutically acceptable salt thereof, COOR.sub.8, or
CONR.sub.9R.sub.10.
10. A compound of claim 5 where Y is phenyl or naphthyl.
11. A compound of claim 10 where R.sub.1 is methyl.
12. A compound of claim 2 where X.sub.1 is --C(R.sub.1).sub.2--O--,
--C(R.sub.1).sub.2--S--, or --C(R.sub.1).sub.2--NR.sub.1--.
13. A compound of claim 12 where R.sub.1 is methyl.
14. A compound of the formula 13where R.sub.1 is independently H or
alkyl of 1 to 6 carbons; R.sub.2 is optional and is defined as
lower alkyl of 1 to 6 carbons, F, Cl, BR, I, CF.sub.3, fluoro
substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6
carbons, or alkylthio of 1 to 6 carbons; n is an integer between 0
and 2; o is an integer between 0 and 3; R.sub.3 is hydrogen, lower
alkyl of 1 to 6 carbons, F, Cl, Br or I; R.sub.4 is
(R.sub.5).sub.p-phenyl, (R.sub.5).sub.p-naphthyl, or
(R.sub.5).sub.p-heteroaryl where the heteroaryl group is pyridyl,
thienyl, furyl or thiazolyl; p is an integer having the values of
0-5; R.sub.5 is optional and is defined as independently F, Cl, Br,
I, NO.sub.2, N(R.sub.8).sub.2, N(R.sub.8)COR.sub.8,
NR.sub.8CON(R.sub.8).sub- .2, OH, OCOR.sub.8, OR.sub.8, CN, COOH,
COOR.sub.8 an alkyl group having 1 to 10 carbons, or fluoro
substituted alkyl group having 1 to 10 carbons; A is
(CH.sub.2).sub.q where q is 0-5, lower branched chain alkyl having
3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6
carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1
or 2 triple bonds, and B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR.sub.8, CONR.sub.9R.sub.10,
--CH.sub.2OH, CH.sub.2OR.sub.11, CH.sub.2OCOR.sub.11, CHO,
CH(OR.sub.12).sub.2, CHOR.sub.13O, --COR.sub.7,
CR.sub.7(OR.sub.12).sub.2, CR.sub.7OR.sub.13O, or
Si(C.sub.1-6alkyl).sub.- 3, where R.sub.7 is an alkyl, cycloalkyl
or alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl
group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl
group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10
carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and
R.sub.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cyloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sub.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of
2-5 carbons.
15. A compound of claim 14 where R.sub.1 is H, there is no optional
R.sub.2, R.sub.3, is H.sub.2 A is (CH.sub.2).sub.q and q is 0, B is
COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, or
CONR.sub.9R.sub.10.
16. A compound of claim 15 where R.sub.4 is 4-methylphenyl.
17. A compound of claim 16 where the phenyl ring is 1,4 (para)
substituted by the A-B and tricyclic groups, and where B is COOH or
a pharmaceutically acceptable salt thereof, or COOR.sub.8 where
R.sub.8 is methyl or ethyl.
18. A compound of claim 15 where R.sub.4 is
6-methyl(3-pyridyl).
19. A compound of claim 18 where the phenyl ring is 1,4 (para)
substituted by the A-B and tricyclic groups, and where B is COOH or
a pharmaceutically acceptable salt thereof, or COOR.sub.8 where
R.sub.8 is methyl or ethyl.
20. A compound of claim 15 where R.sub.4 is
5-methyl(2-thienyl).
21. A compound of claim 20 where the phenyl ring is 1,4 (para)
substituted by the A-B and tricyclic groups, and where B is COOH or
a pharmaceutically acceptable salt thereof, or COOR.sub.8 where
R.sub.8 is methyl or ethyl.
22. A compound of the formula 14where X.sub.1 is O or S; R.sub.2 is
optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl,
Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH,
SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; n is
an integer between 0 and 2; o is an integer between 0 and 3;
R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I;
R.sub.4 is (R.sub.5).sub.p-phenyl, (R.sub.5).sub.p-naphthyl, or
(R.sub.5).sub.p-heteroaryl where the heteroaryl group is pyridyl,
thienyl, furyl or thiazolyl; p is an integer having the values of
0-5; R.sub.5 is optional and is defined as independently F, Cl, Br,
I, NO.sub.2, N(R.sub.8).sub.2, N(R.sub.8)COR.sub.8,
NR.sub.8CON(R.sub.8).sub.2, OH, OCOR.sub.8, OR.sub.8, CN, COOH,
COOR.sub.8 an alkyl group having 1 to 10 carbons, or fluoro
substituted alkyl group having 1 to 10 carbons; A is
(CH.sub.2).sub.q where q is 0-5, lower branched chain alkyl having
3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6
carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1
or 2 triple bonds, and B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, COOR.sub.8, CONR.sub.9R.sub.10,
--CH.sub.2OH, CH.sub.2OR.sub.11, CH.sub.2OCOR.sub.11, CHO,
CH(OR.sub.12).sub.2, CHOR.sub.13O, --COR.sub.7,
CR.sub.7(OR.sub.12).sub.2, CR.sub.7OR.sub.13O, or
Si(C.sub.1-6alkyl).sub.- 3, where R.sub.7 is an alkyl, cycloalkyl
or alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl
group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl
group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10
carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and
R.sub.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sub.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of
2-5 carbons.
23. A compound of claim 22 where there is no optional R.sub.2,
R.sub.3, is H, A is (CH.sub.2).sub.q and q is 0, B is COOH or a
pharmaceutically acceptable salt thereof, COOR.sub.8, or
CONR.sub.9R.sub.10.
24. A compound of claim 23 where X.sub.1 is S.
25. A compound of claim 24 where R.sub.4 is 4-methylphenyl.
26. A compound of claim 25 where the phenyl ring is 1,4 (para)
substituted by the A-B and tricyclic groups, and where B is COOH or
a pharmaceutically acceptable salt thereof, or COOR.sub.8 where
R.sub.8 is methyl or ethyl.
27. A compound of claim 24 where R.sub.4 is
5-methyl(2-thienyl).
28. A compound of claim 27 where the phenyl ring is 1,4 (para)
substituted by the A-B and tricyclic groups, and where B is COOH or
a pharmaceutically acceptable salt thereof, or COOR.sub.8 where
R.sub.8 is methyl or ethyl.
29. A compound of claim 23 where X.sub.1 is O.
30. A compound of claim 29 where R.sub.4 is 4-methylphenyl.
31 A compound of claim 30 where the phenyl ring is 1,4 (para)
substituted by the A-B and tricyclic groups, and where B is COOH or
a pharmaceutically acceptable salt thereof, or COOR.sub.8 where
R.sub.8 is methyl or ethyl.
32 A compound of claim 29 where R.sub.4 is 5-methyl(2-thienyl).
33. A compound of claim 32 where the phenyl ring is 1,4 (para)
substituted by the A-B and tricyclic groups, and where B is COOH or
a pharmaceutically acceptable salt thereof, or COOR.sub.8 where
R.sub.8 is methyl or ethyl.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to novel compounds having
retinoid-like, retinoid antagonist and/or retinoid
inverse-agonist-like biological activity. More specifically, the
present invention relates to aryl or heteroaryl substituted
3,4-dihydroanthracene and aryl or heteroaryl substituted
benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3- -ene and
benzo[1,2-g]-1,2-dihydroquinoline derivatives which bind to
retinoid receptors and have retinoid-like, retinoid antagonist or
retinoid inverse agonist-like biological activity.
[0003] 2. Background Art
[0004] Compounds which have retinoid-like activity are well known
in the art, and are described in numerous United States and other
patents and in scientific publications. It is generally known and
accepted in the art that retinoid-like activity is useful for
treating animals of the mammalian species, including humans, for
curing or alleviating the symptoms and conditions of numerous
diseases and conditions. In other words, it is generally accepted
in the art that pharmaceutical compositions having a retinoid-like
compound or compounds as the active ingredient are useful as
regulators of cell proliferation and differentiation, and
particularly as agents for treating skin-related diseases,
including, actinic keratoses, arsenic keratoses, inflammatory and
non-inflammatory acne, psoriasis, ichthyoses and other
keratinization and hyperproliferative disorders of the skin,
eczema, atopic dermatitis, Darriers disease, lichen planus,
prevention and reversal of glucocorticoid damage (steroid atrophy),
as a topical anti-microbial, as skin anti-pigmentation agents and
to treat and reverse the effects of age and photo damage to the
skin. Retinoid compounds are also useful for the prevention and
treatment of cancerous and precancerous conditions, including,
premalignant and malignant hyperproliferative diseases such as
cancers of the breast, skin, prostate, cervix, uterus, colon,
bladder, esophagus, stomach, lung, larynx, oral cavity, blood and
lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias
and papillomas of the mucous membranes and in the treatment of
Kaposi's sarcoma. In addition, retinoid compounds can be used as
agents to treat diseases of the eye, including, without limitation,
proliferative vitreoretinopathy (PVR), retinal detachment, dry eye
and other corneopathies, as well as in the treatment and prevention
of various cardiovascular diseases, including, without limitation,
diseases associated with lipid metabolism such as dyslipidemias,
prevention of post-angioplasty restenosis and as an agent to
increase the level of circulating tissue plasminogen activator
(TPA). Other uses for retinoid compounds include the prevention and
treatment of conditions and diseases associated with human
papilloma virus (HPV), including warts and genital warts, various
inflammatory diseases such as pulmonary fibrosis, ileitis, colitis
and Krohn's disease, neurodegenerative diseases such as Alzheimer's
disease, Parkinson's disease and stroke, improper pituitary
function, including insufficient production of growth hormone,
modulation of apoptosis, including both the induction of apoptosis
and inhibition of T-Cell activated apoptosis, restoration of hair
growth, including combination therapies with the present compounds
and other agents such as Minoxidil.RTM., diseases associated with
the immune system, including use of the present compounds as
immunosuppressants and immunostimulants, modulation of organ
transplant rejection and facilitation of wound healing, including
modulation of chelosis.
[0005] European Patent Application No. 0 210 929 (published on Feb.
4, 1987) describes polycyclic compounds which are said to have
certain retinoid-like, or related biological activity. U.S. Pat.
Nos. 4,980,369, 5,006,550, 5,015,658, 5,045,551, 5,089,509,
5,134,159, 5,162,546, 5,234,926, 5,248,777, 5,264,578, 5,272,156,
5,278,318, 5,324,744, 5,346,895, 5,346,915, 5,348,972, 5,348,975,
5,380,877, 5,399,561 and 5,407,937, (assigned to the same assignee
as the present application) and patents and publications cited
therein, describe or relate to chroman, thiochroman and
1,2,3,4-tetrahydroquinoline derivatives which have retinoid-like
biological activity.
[0006] U.S. Pat. Nos. 5,130,335; 5,324,840; 5,344,959; 5,451,605;
5,455,265; 5,470,999; 5,475,022; 5,475,113; 5,489,584; 5,514,825;
5,543,534; (assigned to the same assignee as the present
application) and patents and publications cited therein, describe
or relate to 5,6,7,8-tetrahydronaphthalene or naphthalene
derivatives which have retinoid-like biological activity.
[0007] Still further, several co-pending applications and recently
issued patents which are assigned to the assignee of the present
application, are directed to further compounds having retinoid-like
activity.
[0008] Although pharmaceutical compositions containing retinoids
have well established utility (as is demonstrated by the foregoing
citation of patents and publications from the voluminous literature
devoted to this subject) retinoids also cause a number of undesired
side effects at therapeutic dose levels, including headache,
teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity,
dyslipidemias, skin irritation, headache and hepatotoxicity. These
side effects limit the acceptability and utility of retinoids for
treating disease.
[0009] It is now general knowledge in the art that two main types
of retinoid receptors exist in mammals (and other organisms). The
two main types or families of receptors are respectively designated
the RARs and RXRs. Within each type there are subtypes; in the RAR
family the subtypes are designated RAR.sub..alpha., RAR.sub..beta.,
and RAR.sub..gamma., in RXR the subtypes are: RXR.sub..alpha.,
RXB.sub..beta. and RXR.sub..gamma.. It has also been established in
the art that the distribution of the two main retinoid receptor
types, and of the several sub-types is not uniform in the various
tissues and organs of mammalian organisms. Moreover, it is
generally accepted in the art that many unwanted side effects of
retinoids are mediated by one or more of the RAR receptor subtypes.
Accordingly, among compounds having agonist-like activity at
retinoid receptors, specificity or selectivity for one of the main
types or families, and even specificity or selectivity for one or
more subtypes within a family of receptors, is considered a
desirable pharmacological property. Some compounds bind to one or
more RAR receptor subtypes, but do not trigger the response which
is triggered by agonists of the same receptors. A compound that
binds to a biological receptor but does not trigger an agonist-like
response is usually termed an antagonist. Accordingly, the "effect"
of compounds on retinoid receptors may fall in the range of having
no effect at all, (inactive compound, neither agonist nor
antagonist), the compound may elicit an agonist-like response on
all receptor subtypes (pan-agonist), or a compound may be a partial
agonist and/or partial antagonist of certain receptor subtypes if
the compound binds to but does not activate certain receptor
subtype or subtypes but elicits an agonist-like response in other
receptor subtype or subtypes. A pan antagonist is a compound that
binds to all known retinoid receptors but does not elicit an
agonist-like response in any of the receptors.
[0010] Recently a two-state model for certain receptors, including
the above-mentioned retinoid receptors, have emerged. In this
model, an equilibrium is postulated to exist between inactive
receptors and spontaneously active receptors which are capable of
coupling with a G protein in the absence of a ligand (agonist). In
this model, so-called "inverse agonists" shift the equilibrium
toward inactive receptors, thus bringing about an overall
inhibitory effect. Neutral antagonist do not effect the receptor
equilibrium but are capable of competing for the receptors with
both agonists (ligands) and with inverse agonists.
[0011] It has been recently discovered and described in pending
applications assigned to the same assignee as the present
application that the above mentioned retinoid antagonist and/or
inverse agonist-like activity of a compound is also a useful
property, in that such antagonist or inverse agonist-like compounds
can be utilized to block certain undesired side effects of
retinoids, to serve as antidotes to retinoid overdose or poisoning,
and may lend themselves to other pharmaceutical applications as
well. More particularly, regarding the published scientific and
patent literature in this field, published PCT application WO
94/14777 describes certain heterocyclic carboxylic acid derivatives
which bind to RAR retinoid receptors and are said in the
application to be useful for treatment of certain diseases or
conditions, such as acne, psoriasis, rheumatoid arthritis and viral
infections. A similar disclosure is made in the article by
Yoshimura et al. J Med. Chem. 1995, 38, 3163-3173. Kaneko et al.
Med. Chem Res. (1991) 1:220-225; Apfel et al. Proc. Natl. Acad.
Sci. USA Vol 89 pp 7129-7133 August 1992 Cell Biology; Eckhardt et
al. Toxicology Letters, 70 (1994) 299-308; Keidel et al. Molecular
and Cellular Biology, Vol 14, No. 1, Jan. 1994, p 287-298; and
Eyrolles et al. J. Med. Chem. 1994, 37, 1508-1517 describe
compounds which have antagonist like activity at one or more of the
RAR retinoid subtypes.
SUMMARY OF THE INVENTION
[0012] The present invention relates to compounds of Formula 1
2
[0013] wherein X.sub.1 is --C(R.sub.1).sub.2--,
--C(R.sub.1).sub.2--C(R.su- b.1).sub.2--, --S--, --O--,
--NR.sub.1--, --C(R.sub.1).sub.2--O--.
[0014] --C(R.sub.1).sub.2--S--, or
--C(R.sub.1).sub.2--NR.sub.1--;
[0015] R.sub.1 is independently H or alkyl of 1 to 6 carbons;
[0016] R.sub.2 is optional and is defined as lower alkyl of 1 to 6
carbons, F, Cl, Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6
carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6
carbons;
[0017] m is an integer between 0 and 4;
[0018] n is an integer between 0 and 2;
[0019] o is an integer between 0 and 3;
[0020] R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl,
Br or I;
[0021] R.sub.4 is (R.sub.5).sub.p-phenyl, (R.sub.5).sub.p-naphthyl,
or (R.sub.5).sub.p-heteroaryl where the heteroaryl group is
5-membered or 6-membered and has 1 to 3 heteroatoms selected from
the group consisting of O, S and N;
[0022] p is an integer having the values of 0-5;
[0023] R.sub.5 is optional and is defined as independently F, Cl,
Br, I, NO.sub.2, N(R.sub.8).sub.2, N(R.sub.8)COR.sub.8,
NR.sub.8CON(R.sub.8).sub- .2, OH, OCOR.sub.8, OR.sub.8, CN, COOH,
COOR.sub.8 an alkyl group having 1 to 10 carbons, fluoro
substituted alkyl group having 1 to 10 carbons, an alkenyl group
having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group
having 1 to 10 carbons and 1 to 3 triple bonds, or a
(trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups
independently have 1 to 6 carbons;
[0024] Y is a phenyl or naphthyl group, or heteroaryl selected from
a group consisting of pyridyl, thienyl, furyl, pyridazinyl,
pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and
pyrrazolyl, said phenyl and heteroaryl groups being optionally
substituted with one or two R.sub.2 groups, or Y is
--(CR.sub.3.dbd.CR.sub.3).sub.r--;
[0025] r is an integer between 1 and 3;
[0026] A is (CH.sub.2).sub.q where q is 0-5, lower branched chain
alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl
having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6
carbons and 1 or 2 triple bonds, with the proviso that when Y is
--(CR.sub.3.dbd.C.sub.3).su- b.r-- then A is (CH.sub.2).sub.q and q
is 0;
[0027] B is hydrogen, COOH or a pharmaceutically acceptable salt
thereof, COOR.sub.8, CONR.sub.9R.sub.10, --CH.sub.2OH,
CH.sub.2OR.sub.11, CH.sub.2OCOR.sub.11, CHO, CH(OR.sub.12).sub.2,
CHOR.sub.13O, --COR.sub.7, CR.sub.7(OR.sub.12).sub.2,
CR.sub.7OR.sub.13O, or Si(C.sub.1-6alkyl).sub.- 3, where R.sub.7 is
an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
R.sub.8 is an alkyl group of 1 to 10 carbons or
(trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or
a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or
lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen,
an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10
carbons, or phenyl or lower alkylphenyl, R.sub.11 is lower alkyl,
phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13
is divalent alkyl radical of 2-5 carbons.
[0028] In a second aspect, this invention relates to the use of the
compounds of Formula 1 for the treatment of skin-related diseases,
including, without limitation, actinic keratoses, arsenic
keratoses, inflammatory and non-inflammatory acne, psoriasis,
ichthyoses and other keratinization and hyperproliferative
disorders of the skin, eczema, atopic dermatitis, Darriers disease,
lichen planus, prevention and reversal of glucocorticoid damage
(steroid atrophy), as a topical anti-microbial, as skin
anti-pigmentation agents and to treat and reverse the effects of
age and photo damage to the skin. The compounds are also useful for
the prevention and treatment of cancerous and precancerous
conditions, including, premalignant and malignant
hyperproliferative diseases such as cancers of the breast, skin,
prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,
larynx, oral cavity, blood, and lymphatic system, metaplasias,
dysplasias, neoplasias, leukoplakias and papillomas of the mucous
membranes and in the treatment of Kaposi's sarcoma. In addition,
the present compounds can be used as agents to treat diseases of
the eye, including, without limitation, proliferative
vitreoretinopathy (PVR), retinal detachment, dry eye and other
corneopathies, as well as in the treatment and prevention of
various cardiovascular diseases, including, without limitation,
diseases associated with lipid metabolism such as dyslipidemias,
prevention of post-angioplasty restenosis and as an agent to
increase the level of circulating tissue plasminogen activator
(TPA). Other uses for the compounds of the present invention
include the prevention and treatment of conditions and diseases
associated with Human papilloma virus (HPV), including warts and
genital warts, various inflammatory diseases such as pulmonary
fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative
diseases such as Alzheimer's disease, Parkinson's disease and
stroke, improper pituitary function, including insufficient
production of growth hormone, modulation of apoptosis, including
both the induction of apoptosis and inhibition of T-Cell activated
apoptosis, restoration of hair growth, including combination
therapies with the present compounds and other agents such as
Minoxidil.RTM., diseases associated with the immune system,
including use of the present compounds as immunosuppressants and
immunostimulants, modulation of organ transplant rejection and
facilitation of wound healing, including modulation of
chelosis.
[0029] Alternatively, those compounds of the invention which act as
antagonists or inverse agonists of one or more retinoid receptor
subtypes are useful to prevent certain undesired side effects of
retinoids which are administered for the treatment or prevention of
certain diseases or conditions. For this purpose the retinoid
antagonist and/or inverse agonist compounds of the invention may be
co-administered with retinoids. The retinoid antagonist and inverse
agonist compounds of the present invention are also useful in the
treatment of acute or chronic toxicity resulting from overdose or
poisoning by retinoid drugs or Vitamin A.
[0030] This invention also relates to a pharmaceutical formulation
comprising a compound of Formula 1 in admixture with a
pharmaceutically acceptable excipient, said formulation being
adapted for administration to a mammal, including a human being, to
treat or alleviate the conditions which were described above as
treatable by retinoids, to be co-administered with retinoids to
eliminate or reduce side effects of retinoids, or to treat retinoid
or Vitamin A overdose or poisoning.
Biological Activity, Modes of Administration
[0031] Assay of Retinoid-like or Retinoid Antagonist and Inverse
Agonist-like Biological Activity
[0032] A classic measure of retinoic acid activity involves
measuring the effects of retinoic acid on ornithine decarboxylase.
The original work on the correlation between retinoic acid and
decrease in cell proliferation was done by Verma & Boutwell,
Cancer Research, 1977, 37, 2196-2201. That reference discloses that
ornithine decarboxylase (ODC) activity increased precedent to
polyamine biosynthesis. It has been established elsewhere that
increases in polyamine synthesis can be correlated or associated
with cellular proliferation. Thus, if ODC activity could be
inhibited, cell hyperproliferation could be modulated. Although all
cases for ODC activity increases are unknown, it is known that
12-0-tetradecanoylphorbo- l-13-acetate (TPA) induces ODC activity.
Retinoic acid inhibits this induction of ODC activity by TPA. An
assay essentially following the procedure set out in Cancer
Research: 1662-1670,1975 may be used to demonstrate inhibition of
TPA induction of ODC by compounds of this invention. "IC.sub.60" is
that concentration of the test compound which causes 60% inhibition
in the ODC assay. By analogy, "IC.sub.80", for example, is that
concentration of the test compound which causes 80% inhibition in
the ODC assay.
[0033] Other assays described below, measure the ability of the
compounds of the present invention to bind to, and/or activate
various retinoid receptor subtypes. When in these assays a compound
binds to a given receptor subtype and activates the transcription
of a reporter gene through that subtype, then the compound is
considered an agonist of that receptor subtype. Conversely, a
compound is considered an antagonist of a given receptor subtype if
in the below described co-tranfection assays the compound does not
cause significant transcriptional activation of the receptor
regulated reporter gene, but nevertheless binds to the receptor
with a K.sub.d value of less than approximately 1 micromolar. In
the below described assays the ability of the compounds to bind to
RAR.sub..alpha., RAR.sub..beta., RAR.sub..gamma., RXR.sub..alpha.,
RXR.sub..beta. and RXR.sub..GAMMA. receptors, and the ability or
inability of the compounds to activate transcription of a reporter
gene through these receptor subtypes can be tested.
[0034] Specifically, a chimeric receptor transactivation assay
which tests for agonist-like activity in the RAR.sub..alpha.,
RAR.sub..beta., RAR.sub..gamma., RXR.sub..alpha. receptor subtypes,
and which is based on work published by Feigner P. L. and Holm M.
(1989) Focus, 11 2 is described in detail in U.S. Pat. No.
5,455,265 the specification of which is hereby expressly
incorporated by reference.
[0035] A holoreceptor transactivation assay and a ligand binding
assay which measure the antagonist/agonist like activity of the
compounds of the invention, or their ability to bind to the several
retinoid receptor subtypes, respectively, are described in
published PCT Application No. WO WO93/11755 (particularly on pages
30-33 and 37-41) published on Jun. 24, 1993, the specification of
which is also incorporated herein by reference. A description of
the holoreceptor transactivation assay is also provided below.
[0036] Holoreceptor Transactivation Assay
[0037] CV1 cells (5,000 cells/well) were transfected with an RAR
reporter plasmid MTV-TREp-LUC (50 ng) along with one of the RAR
expression vectors (10 ng) in an automated 96-well format by the
calcium phosphate procedure of Heyman et al. Cell 68, 397-406,
(1992). For RXR.sub..alpha. and RXR.sub..gamma. transactivation
assays, an RXR-responsive reporter plasmid CRBPII-tk-LUC (50 ng)
along with the appropriate RXR expression vectors (10 ng) was used
substantially as described by Heyman et al. above, and Allegretto
et al. J. Biol. Chem. 268, 26625-26633. For RXR.sub..beta.
transactivation assays, an RXR-responsive reporter plasmid
CPRE-tk-LUC (50 mg) along with RXR.sub..beta. expression vector (10
mg) was used as described in above. These reporters contain DRI
elements from human CRBPII and certain DRI elements from promoter,
respectively. (see Mangelsdorf et al. The Retinoids: Biology,
Chemistry and Medicine, pp 319-349, Raven Press Ltd., New York and
Heyman et al., cited above) (1, 8). A .beta.-galactosidase (50 ng)
expression vector was used as an internal control in the
transfections to normalize for variations in transfection
efficiency. The cells were transfected in triplicate for 6 hours,
followed by incubation with retinoids for 36 hours, and the
extracts were assayed for luciferase and .beta.-galactosidase
activities, The detailed experimental procedure for holoreceptor
transactivations has been described in Heyman et al. above, and
Allegretto et al. cited above. The results obtained in this assay
are expressed in EC.sub.50 numbers, as they are also in the
chimeric receptor transactivation assay. The Heyman et al. Cell 68,
397-406, Allegretto et al. J. Biol. Chem. 268, 26625-26633, and
Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine,
pp 319-349, Raven Press Ltd., New York, are expressly incorporated
herein by reference. The results of ligand binding assay are
expressed in K.sub.d numbers. (See Cheng et al. Biochemical
Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by
reference.)
[0038] Table 1 shows the results of the ligand binding assay for
certain exemplary compounds of the invention for the receptor
subtypes in the RAR group.
1TABLE 1 Ligand Binding Assay Compound K.sub.d (nanomolar, nM) No.
RAR.alpha. RAR.beta. TAT.gamma. 2 13 4 7 4 15 6 11 12 17 12 33
[0039] Inverse agonists are ligands that are capable of inhibiting
the basal receptor activity of unliganded receptors. Recently,
retinoic acid receptors (RARs) have been shown to be responsive to
retinoid inverse agonists in regulating basal gene transcriptional
activity. Moreover, the biological effects associated with retinoid
inverse agonists are distinct from those of retinoid agonists or
antagonists. For example, RAR inverse agonists, but not RAR neutral
antagonists, cause a dose-dependent inhibition of the protein MRP-8
in cultured human keratinocytes differentiated with serum. MRP-8 is
a specific marker of cell differentiation, which is also highly
expressed in psoriatic epidermis, but is not detectable in normal
human skin. Thus, retinoid inverse agonists may offer a unique way
of treating diseases such as psoriasis.
[0040] The activity of retinoid inverse agonists can be tested by
the procedure of Klein et al. J. Biol. Chem. 271, 22692-22696
(1996) which is expressly incorporated herein by reference.
[0041] In this assay, retinoid inverse agonists are able to repress
the basal activity of a RAR.gamma.-VP-16 chimeric receptor where
the constituitively active domain of the herpes simplex virus (HSV)
VP-16 is fused to the N-terminus of RAR.gamma.. CV-1 cells are
cotransfected with RAR.gamma.-VP-16, an ER-RXR.alpha. chimeric
receptor and an ERE-tk-Luc chimeric reporter gene to produce a
basal level of luciferase activity, as shown by Nagpal et al. EMBO
J. 12, 2349-2360 (1933) expressly incorporated herein by reference.
Retinoid inverse agonists are able to inhibit the basal luciferase
activity in these cells in a dose dependent manner and IC.sub.50s
measured. In this assay, Compound 2 had an IC.sub.50 of 1.0 nM.
[0042] Modes of Administration
[0043] The compounds of this invention may be administered
systemically or topically, depending on such considerations as the
condition to be treated, need for site-specific treatment, quantity
of drug to be administered, and numerous other considerations.
[0044] In the treatment of dermatoses, it will generally be
preferred to administer the drug topically, though in certain cases
such as treatment of severe cystic acne or psoriasis, oral
administration may also be used. Any common topical formulation
such as a solution, suspension, gel, ointment, or salve and the
like may be used. Preparation of such topical formulations are well
described in the art of pharmaceutical formulations as exemplified,
for example, by Remington's Pharmaceutical Science, Edition 17,
Mack Publishing Company, Easton, Pa. For topical application, these
compounds could also be administered as a powder or spray,
particularly in aerosol form. If the drug is to be administered
systemically, it may be confected as a powder, pill, tablet or the
like or as a syrup or elixir suitable for oral administration. For
intravenous or intraperitoneal administration, the compound will be
prepared as a solution or suspension capable of being administered
by injection. In certain cases, it may be useful to formulate these
compounds by injection. In certain cases, it may be useful to
formulate these compounds in suppository form or as extended
release formulation for deposit under the skin or intramuscular
injection.
[0045] Other medicaments can be added to such topical formulation
for such secondary purposes as treating skin dryness; providing
protection against light; other medications for treating
dermatoses; medicaments for preventing infection, reducing
irritation, inflammation and the like.
[0046] Treatment of dermatoses or any other indications known or
discovered to be susceptible to treatment by retinoic acid-like
compounds will be effected by administration of the therapeutically
effective dose of one or more compounds of the instant invention. A
therapeutic concentration will be that concentration which effects
reduction of the particular condition, or retards its expansion. In
certain instances, the compound potentially may be used in
prophylactic manner to prevent onset of a particular condition.
[0047] A useful therapeutic or prophylactic concentration will vary
from condition to condition and in certain instances may vary with
the severity of the condition being treated and the patient's
susceptibility to treatment. Accordingly, no single concentration
will be uniformly useful, but will require modification depending
on the particularities of the disease being treated. Such
concentrations can be arrived at through routine experimentation.
However, it is anticipated that in the treatment of, for example,
acne, or similar dermatoses, that a formulation containing between
0.01 and 1.0 milligrams per milliliter of formulation will
constitute a therapeutically effective concentration for total
application. If administered systemically, an amount between 0.01
and 5 mg per kg per day of body weight would be expected to effect
a therapeutic result in the treatment of many diseases for which
these compounds are useful.
[0048] The partial or pan retinoid antagonist and/or retinoid
inverse agonist compounds of the invention, when used to take
advantage of their antagonist and/or inverse agonist property, can
be co-administered to mammals, including humans, with retinoid
agonists and, by means of pharmacological selectivity or
site-specific delivery, preferentially prevent the undesired
effects of certain retinoid agonists. The antagonist and/or inverse
agonist compounds of the invention can also be used to treat
Vitamin A overdose, acute or chronic, resulting either from the
excessive intake of vitamin A supplements or from the ingestion of
liver of certain fish and animals that contain high levels of
Vitamin A. Still further, the antagonist and/or inverse agonist
compounds of the invention can also be used to treat acute or
chronic toxicity caused by retinoid drugs. It has been known in the
art that the toxicities observed with hypervitaminosis A syndrome
(headache, skin peeling, bone toxicity, dyslipidemias) are similar
or identical with toxicities observed with other retinoids,
suggesting a common biological cause, that is RAR activation.
Because the antagonist or inverse agonist compounds of the present
invention block or diminish RAR activation, they are suitable for
treating the foregoing toxicities.
[0049] Generally speaking, for therapeutic applications in mammals,
the antagonist and/or inverse agonist compounds of the invention
can be admistered enterally or topically as an antidote to vitamin
A, or antidote to retinoid toxicity resulting from overdose or
prolonged exposure, after intake of the causative factor (vitamin
A, vitamin A precursor, or other retinoid) has been discontinued.
Alternatively, the antagonist and/or inverse agonist compounds of
the invention are co-administered with retinoid drugs, in
situations where the retinoid provides a therapeutic benefit, and
where the co-administered antagonist and/or inverse agonist
compound alleviates or eliminates one or more undesired side
effects of the retinoid. For this type of application the
antagonist and/or inverse agonist compound may be administered in a
site-specific manner, for example as a topically applied cream or
lotion while the co-administered retinoid may be given enterally.
For therapeutic applications the antagonist compounds of the
invention, like the retinoid agonists compounds, are incorporated
into pharmaceutical compositions, such as tablets, pills, capsules,
solutions, suspensions, creams, ointments, gels, salves, lotions
and the like, using such pharmaceutically acceptable excipients and
vehicles which per se are well known in the art. For topical
application, the antagonist and/or inverse agonist compounds of the
invention could also be administered as a powder or spray,
particularly in aerosol form. If the drug is to be administered
systemically, it may be confected as a powder, pill, tablet or the
like or as a syrup or elixir suitable for oral administration. For
intravenous or intraperitoneal administration, the compound will be
prepared as a solution or suspension capable of being administered
by injection. In certain cases, it may be useful to formulate these
compounds by injection. In certain cases, it may be useful to
formulate these compounds in suppository form or as extended
release formulation for deposit under the skin or intramuscular
injection.
[0050] The antagonist and/or inverse agonist compounds also, like
the retinoid agonists of the invention, will be administered in a
therapeutically effective dose. A therapeutic concentration will be
that concentration which effects reduction of the particular
condition, or retards its expansion. When co-administering the
compounds of the invention to block retinoid-induced toxicity or
side effects, the antagonist and/or inverse agonist compounds of
the invention are used in a prophylactic manner to prevent onset of
a particular condition, such as skin irritation.
[0051] A useful therapeutic or prophylactic concentration will vary
from condition to condition and in certain instances may vary with
the severity of the condition being treated and the patient's
susceptibility to treatment. Accordingly, no single concentration
will be uniformly useful, but will require modification depending
on the particularities of the chronic or acute retinoid toxicity or
related condition being treated. Such concentrations can be arrived
at through routine experimentation. However, it is anticipated that
a formulation containing between 0.01 and 1.0 milligrams of the
active compound per mililiter of formulation will constitute a
therapeutically effective concentration for total application. If
administered systemically, an amount between 0.01 and 5 mg per kg
per day of body weight would be expected to effect a
General Embodiments and Synthetic Methodology
[0052] Definitions
[0053] The term alkyl refers to and covers any and all groups which
are known as normal alkyl, branched-chain alkyl and cycloalkyl. The
term alkenyl refers to and covers normal alkenyl, branch chain
alkenyl and cycloalkenyl groups having one or more sites of
unsaturation. Similarly, the term alkynyl refers to and covers
normal alkynyl, and branch chain alkynyl groups having one or more
triple bonds.
[0054] Lower alkyl means the above-defined broad definition of
alkyl groups having 1 to 6 carbons in case of normal lower alkyl,
and as applicable 3 to 6 carbons for lower branch chained and
cycloalkyl groups. Lower alkenyl is defined similarly having 2 to 6
carbons for normal lower alkenyl groups, and 3 to 6 carbons for
branch chained and cyclo- lower alkenyl groups. Lower alkynyl is
also defined similarly, having 2 to 6 carbons for normal lower
alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl
groups.
[0055] The term "ester" as used here refers to and covers any
compound falling within the definition of that term as classically
used in organic chemistry. It includes organic and inorganic
esters. Where B of Formula 1 is --COOH, this term covers the
products derived from treatment of this function with alcohols or
thiols preferably with aliphatic alcohols having 1-6 carbons. Where
the ester is derived from compounds where B is --CH.sub.2OH, this
term covers compounds derived from organic acids capable of forming
esters including phosphorous based and sulfur based acids, or
compounds of the formula --CH.sub.2OCOR.sub.11 where R.sub.11 is
any substituted or unsubstituted aliphatic, aromatic,
heteroaromatic or aliphatic aromatic group, preferably with 1-6
carbons in the aliphatic portions.
[0056] Unless stated otherwise in this application, preferred
esters are derived from the saturated aliphatic alcohols or acids
of ten or fewer carbon atoms or the cyclic or saturated aliphatic
cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly
preferred aliphatic esters are those derived from lower alkyl acids
and alcohols. Also preferred are the phenyl or lower alkyl phenyl
esters.
[0057] Amides has the meaning classically accorded that term in
organic chemistry. In this instance it includes the unsubstituted
amides and all aliphatic and aromatic mono- and di- substituted
amides. Unless stated otherwise in this applications preferred
amides are the mono- and di-substituted amides derived from the
saturated aliphatic radicals of ten or fewer carbon atoms or the
cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon
atoms. Particularly preferred amides are those derived from
substituted and unsubstituted lower alkyl amines. Also preferred
are mono- and disubstituted amides derived from the substituted and
unsubstituted phenyl or lower alkylphenyl amines. Unsubstituted
amides are also preferred.
[0058] Acetals and ketals include the radicals of the formula-CK
where K is (--OR).sub.2. Here, R is lower alkyl. Also, K may be
--OR.sub.7O-- where R.sub.7 is lower alkyl of 2-5 carbon atoms,
straight chain or branched.
[0059] A pharmaceutically acceptable salt may be prepared for any
compounds in this invention having a functionality capable of
forming a salt, for example an acid functionality. A
pharmaceutically acceptable salt is any salt which retains the
activity of the parent compound and is does not impart any
deleterious or untoward effect on the subject to which it is
administered and in the context in which it is administered.
[0060] Pharmaceutically acceptable salts may be derived from
organic or inorganic bases. The salt may be a mono or polyvalent
ion. Of particular interest are the inorganic ions, sodium,
potassium, calcium, and magnesium. Organic salts may be made with
amines, particularly ammonium salts such as mono-, di- and trialkyl
amines or ethanol amines. Salts may also be formed with caffeine,
tromethamine and similar molecules. Where there is a nitrogen
sufficiently basic as to be capable of forming acid addition salts,
such may be formed with any inorganic or organic acids or
alkylating agent such as methyl iodide. Preferred salts are those
formed with inorganic acids such as hydrochloric acid, sulfuric
acid or phosphoric acid. Any of a number of simple organic acids
such as mono-, di- or tri- acid may also be used.
[0061] Some of the compounds of the present invention may have
trans and cis (E and Z) isomers. In addition, the compounds of the
present invention may contain one or more chiral centers and
therefore may exist in enantiomeric and diastereomeric forms. The
scope of the present invention is intended to cover all such
isomers per se, as well as mixtures of cis and trans isomers,
mixtures of diastereomers and racemic mixtures of enantiomers
(optical isomers) as well. In the present application when no
specific mention is made of the configuration (cis, trans, or R or
S) of a compound (or of an asymmetric carbon) then a mixture of
such isomers, or either one of the isomers is intended. In a
similar vein, when in the chemical structural formulas of this
application a straight line representing a valence bond is drawn to
an asymmetric carbon, then isomers of both R and S configuration,
as well as their mixtures are intended.
[0062] The numbering system used in the naming of the compounds of
the present invention, as well as of the intermediate compounds
utilized in the synthetic routes leading to the compounds of the
invention, is illustrated below for 3,4-dihydroanthracene,
benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and
benzo[1,2-g]-1,2-dihydroquinoline and for
3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone. 3
[0063] 3,4-dihydroanthracene benzo[1,2-g]-chrom-3-en
benzo[1,2-g]-thiochrom-3-en 4
[0064] benzo[1,2g-]-1,2dihydroquinoline
3,4-dihydro4,4dimethyl-7-bromo-1(2- H)-naphthalenone
[0065] Generally speaking, the 3,4-dihydroanthracene compounds of
the invention are prepared in synthetic steps which usually first
involve the multistep preparation of a 3,4-dihydronaphthalene
derivative that already includes the desired R.sub.1, R.sub.2,
R.sub.3 and R.sub.4 substituents and an aldehyde function in the 6
or 7-position of the 3,4-dihydronaphthalene nucleus. For the
preparation of benzo[1,2-g]-chrom-3-ene,
benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline
derivatives of the invention, the first (usually multi-step)
procedure involves the preparation of a chrom-3-ene,
thiochrom-3-ene or 1,2-dihydroquinoline derivative which already
includes the desired R.sub.1, R.sub.2, R.sub.3 and R.sub.4
substituents of the compounds of the invention, and an aldehyde
function in the 6 or 7-position of the chrom-3-ene, thiochrom-3-ene
or 1,2-dihydroquinoline nucleus. The aldehyde is then reacted in a
Horner Emmons or Wittig, or like reaction with an aryl or
heteroaryl phosphonate that carries a side chain capable of
cyclizing with the carbocyclic aromatic group of the
3,4-dihydronaphthalene, chrom-3-ene, thiochrom-3-ene or
1,2-dihydroquinoline intermediate. The latter cyclization reaction
forms the "C" ring of the 3,4-dihydroanthracene,
benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and
benzo[1,2-g]-1,2-dihydroquinoline compounds of the invention.
[0066] Details of the above-outlined generalized synthetic schemes
are provided below in connection with the description of the
specific embodiments and specific examples.
[0067] The synthetic methodology employed for the synthesis of the
compounds of the present invention may also include transformations
of the group designated -A-B in Formula 1. Generally speaking,
these transformations involve reactions well within the skill of
the practicing organic chemist. In this regard the following well
known and published general principles and synthetic methodology
are briefly described.
[0068] Carboxylic acids are typically esterified by refluxing the
acid in a solution of the appropriate alcohol in the presence of an
acid catalyst such as hydrogen chloride or thionyl chloride.
Alternatively, the carboxylic acid can be condensed with the
appropriate alcohol in the presence of dicyclohexylcarbodiimide
(DCC) and 4-(dimethylamino)pyridine (DMAP). The ester is recovered
and purified by conventional means. Acetals and ketals are readily
made by the method described in March, "Advanced Organic
Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810).
Alcohols, aldehydes and ketones all may be protected by forming
respectively, ethers and esters, acetals or ketals by known methods
such as those described in McOmie, Plenum Publishing Press, 1973
and Protecting Groups, Ed. Greene, John Wiley & Sons, 1981.
[0069] To increase the value of q in the compounds of the invention
(or precursors thereof) before affecting the coupling or linkage in
a Horner Emmons or like reaction with the aldehyde on the
3,4-dihydronaphthalene, chrom-3-ene, thiochrom-3-ene or
1,2-dihydroquinoline nucleus (where such compounds are not
available from a commercial source) aromatic or heteroaromatic
carboxylic acids are subjected to homologation by successive
treatment under Arndt-Eistert conditions or other homologation
procedures. Alternatively, derivatives which are not carboxylic
acids may also be homologated by appropriate procedures. The
homologated acids can then be esterified by the general procedure
outlined in the preceding paragraph and converted into phosphonates
of phosphonium salts suitable for the Horner Emmons or Witig
reaction. Compounds of the invention as set forth in Formula 1 (or
precursors thereof) where A is an alkenyl group having one or more
double bonds can be made for example, by synthetic schemes well
known to the practicing organic chemist; for example by Wittig and
like reactions, or by introduction of a double bond by elimination
of halogen from an alpha-halo-arylalkyl-carboxylic acid, ester or
like carboxaldehyde. Compounds of the invention or precursors
thereof, where the A group has a triple (acetylenic) bond, can be
made by reaction of a corresponding aromatic methyl ketone with
strong base, such as lithium diisopropylamide, reaction with
diethyl chlorophosphate and subsequent addition of lithium
diisopropylamide.
[0070] The acids and salts derived from compounds of the invention
are readily obtainable from the corresponding esters. Basic
saponification with an alkali metal base will provide the acid. For
example, an ester of the invention may be dissolved in a polar
solvent such as an alkanol, preferably under an inert atmosphere at
room temperature, with about a three molar excess of base, for
example, lithium hydroxide or potassium hydroxide. The solution is
stirred for an extended period of time, between 15 and 20 hours,
cooled, acidified and the hydrolysate recovered by conventional
means.
[0071] The amide may be formed by any appropriate amidation means
known in the art from the corresponding esters or carboxylic acids.
One way to prepare such compounds is to convert an acid to an acid
chloride and then treat that compound with ammonium hydroxide or an
appropriate amine. For example, the ester is treated with an
alcoholic base solution such as ethanolic KOH (in approximately a
10% molar excess) at room temperature for about 30 minutes. The
solvent is removed and the residue taken up in an organic solvent
such as diethyl ether, treated with a dialkyl formamide and then a
10-fold excess of oxalyl chloride. This is all effected at a
moderately reduced temperature between about -10 degrees and +10
degrees C. The last mentioned solution is then stirred at the
reduced temperature for 1-4 hours, preferably 2 hours. Solvent
removal provides a residue which is taken up in an inert organic
solvent such as benzene, cooled to about 0 degrees C. and treated
with concentrated ammonium hydroxide. The resulting mixture is
stirred at a reduced temperature for 1-4 hours. The product is
recovered by conventional means.
[0072] Alcohols are made by converting the corresponding acids to
the acid chloride with thionyl chloride or other means (J. March,
"Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book
Company), then reducing the acid chloride with sodium borohydride
(March, Ibid, pg. 1124), which gives the corresponding alcohols.
Alternatively, esters may be reduced with lithium aluminum hydride
at reduced temperatures. Alkylating these alcohols with appropriate
alkyl halides under Williamson reaction conditions (March, Ibid,
pg. 357) gives the corresponding ethers. These alcohols can be
converted to esters by reacting them with appropriate acids in the
presence of acid catalysts or dicyclohexylcarbodiimide and
dimethylaminopyridine.
[0073] Aldehydes can be prepared from the corresponding primary
alcohols using mild oxidizing agents such as pyridinium dichromate
in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett., 399,
1979), or dimethyl sulfoxide/oxalyl chloride in methylene chloride
(Omura, K., Swern, D., Tetrahedron, 1978, 34, 1651).
[0074] Ketones can be prepared from an appropriate aldehyde by
treating the aldehyde with an allyl Grignard reagent or similar
reagent followed by oxidation.
[0075] Acetals or ketals can be prepared from the corresponding
aldehyde or ketone by the method described in March, Ibid, p
810.
[0076] Compounds of the invention, or precursors thereof, where B
is H can be prepared from the corresponding halogenated aromatic or
heteroaromatic compounds, preferably where the halogen is I.
Specific Embodiments
[0077] With reference to-the symbol Y in Formula 1, the preferred
compounds of the invention are those where Y is phenyl, naphthyl,
pyridyl, thienyl or furyl. Even more preferred are compounds where
Y is phenyl. As far as substititutions on the Y (phenyl) and Y
(pyridyl) groups are concerned, compounds are preferred where the
phenyl group is 1,4 para) substituted and where the pyridine ring
is 2,5 substituted. (Substitution in the 2,5 positions in the
"pyridine" nomenclature corresponds to substitution in the
6-position in the "nicotinic acid" nomenclature.) In the presently
preferred compounds of the invention there is no R.sub.2
substituent on the Y group.
[0078] The A-B group of the preferred compounds is
(CH.sub.2).sub.qCOOH or (CH.sub.2).sub.q--COOR.sub.8, where R.sub.8
is defined as above. Even more preferably q is zero and R.sub.8 is
lower alkyl.
[0079] The aromatic carbocyclic portions (B and C rings) of the
3,4-dihydroanthracene moiety, or of the benzo[1,2-g]-chrom-3-ene,
benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline
moiety of the compounds of the invention (as applicable) are
preferably substituted only by the --Y(R.sub.2).sub.m-A-B group. In
other words, in the preferred compounds there is no R.sub.2
substituent (other than hydrogen) on the aromatic carbocyclic
portion of the condensed ring system. Similarly, in the preferred
compounds of the invention there is no R.sub.3 substituent (other
than hydrogen).
[0080] The moiety designated X.sub.1 in Formula 1 is preferably
--C(R.sub.1).sub.2-- C(R.sub.1).sub.2--, --C(R.sub.1).sub.2--O--,
--C(R.sub.1).sub.2--NR.sub.1--, and R.sub.1 is preferably H or
methyl. The --Y(R.sub.2).sub.m-A-B group is preferably attached to
the 8-position of the 3,4-dihydroanthracene nucleus and to the
7-position of the benzo[1,2-g]-chrom-3-ene,
benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline
nucleus, as applicable.
[0081] Referring now to the R.sub.4 substituent in the compounds of
Formula 1, compounds are preferred where this substituent is
phenyl, R.sub.5-substituted phenyl, pyridyl, R.sub.5-substituted
pyridyl, thienyl, or R.sub.5-substituted thienyl. Even more
preferred are compounds where the R.sub.4 substituent is phenyl,
4-methylphenyl, 3-pyridyl and particularly 6-methyl-3-pyridyl,
2-thienyl and particularly 5-methyl-2-thienyl.
[0082] The most preferred compounds of the invention are listed
below in Table 2 with reference to Formula 2 or Formula 3, as
applicable. 5 6
2TABLE 2 Compound No. Formula X.sub.1* R.sub.4* R.sub.8* 1 2 --
4-methylphenyl Et 2 2 -- 4-methylphenyl H 3 2 --
5-methyl(2-thienyl) Et 4 2 -- 5-methyl(2-thienyl) H 5 2 --
6-methyl(3-pyridyl) Et 6 2 -- 6-methyl(3-pyridyl) H 7 3 S
4-methylphenyl Et 8 3 S 4-methylphenyl H 9 3 O 4-methylphenyl Et 10
3 O 4-methylphenyl H 11 3 O 5-methyl(2-thienyl) Et 12 3 O
5-methyl(3-thienyl) H 13 3 S 5-methyl(2-thienyl) Et 14 3 S
5-methyl(2-thienyl) H
[0083] The compounds of this invention can be made by the general
procedures outlined above under the title ""GENERAL EMBODIMENTS AND
SYNTHETIC METHODOLOGY". The following chemical pathways represent
the presently preferred synthetic routes to certain classes of the
compounds of the invention and to certain specific exemplary
compounds. However, the synthetic chemist will readily appreciate
that the conditions set out here for these specific embodiments can
be generalized to any and all of the compounds represented by
Formula 1. 7
[0084] Referring now to Reaction Scheme 1 a synthetic process is
described whereby compounds of the invention are obtained in which,
with reference to Formula 1, X.sub.1 is
--C(R.sub.1).sub.2--C(R.sub.1).sub.2-- and the Y group is phenyl,
naphthyl or heteroaryl. In other words Reaction Scheme 1 describes
an example of a synthetic route for preparing compounds of the
invention which are 3,4-dihydroanthracene derivatives. The reaction
scheme discloses this synthetic route for the preferred examples in
which the Y group is coupled to the 8 position of the
3,4-dihydroanthracene nucleus, and the 4-position bears two
(geminal) methyl substituents. Nevertheless, those skilled in the
art will readily understand that the synthetic steps of Reaction
Scheme 1 can be readily modified, within the skill of the art, to
yield other 3,4-dihydroanthracene compounds of the invention. The
starting materials for the synthetic route of Reaction Scheme 1 are
6 or 7-bromo (or like halogeno) substituted 1-(2H)-naphthalenones.
Specifically, for the examplary synthetic route illustrated in
Reaction Scheme 1 the starting material is
3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A).
Compound A can be obtained in accordance with the chemical
scientific (Johnson et al. , J. Med. Chem. 1995, 38, 4764-4767) and
patent (U.S. Pat. No. 5,543,534) literature. The Johnson et al.
publication and the specification of U.S. Pat. No. 5,543,534 are
expressly incorporated herein by reference. Another example for the
starting material in Reaction Scheme 1 is
3,4-dihydro-4,4-dimethyl-6-bromo-1(2H)-naphthalenone- . The latter
compound, when subjected to the reactions disclosed in this scheme,
gives rise to 3,4-dihydroanthracene compounds of the invention
where the Y group is coupled to the 7-position of the
3,4-dihydroanthracene nucleus.
3,4-Dihydro-4,4-dimethyl-6-bromo-1(2H)-nap- hthalenone can also be
obtained in accordance with the chemical scientific (Mathur et al.
Tetrahedron, 41, 1509 1516 (1985)) and patent (U.S. Pat. No.
5,543,534) literature.
[0085] In accordance with Reaction Scheme 1,
3,4-dihydro-4,4-dimethyl-7-br- omo-1(2H)-naphthalenone (Compound A)
is reacted with a Grignard reagent of the formula
R.sub.4-Mg-X.sub.2, where R.sub.4 is an aryl or heteroaryl group as
defined in connection with Formula 1, and X.sub.2 is halogen,
preferably bromine. The product of the Grignard (or analogous)
reaction is a tertiary alcohol (not shown in the reaction scheme)
which is dehydrated by treatment with acid, to give a 1-aryl or
1-heteroaryl-7-bromo-3,4-dihydronaphthalene derivative of Formula
4. An example for a Grignard reagent used in the synthesis of
preferred compounds of the invention is the reagent obtained from
4-bromotoluene with magnesium. An alternative method for obtaining
the 1-aryl or 1-heteroaryl-7-bromo-3,4-dihydronaphthalene
derivatives of Formula 4 is a reaction between an aryl or
heteroaryl halide of the formula R.sub.4--X.sub.2 (R.sub.4 and
X.sub.2 are defined as above, X.sub.2 is preferably Br) with
Compound A in the presence of strong base, such as n-butyl lithium.
A suitable reagent for this reaction is, for example,
2-methyl-5-bromopyridine. As still another alternative, Compound A
is reacted with the lithium (or other suitable metal) salt of the
formula R.sub.4--Li, (R.sub.4 is defined as above), that can be
obtained by reaction between a heteroaryl compound (such as
2-methylthiophene) and n-butyl lithium.
[0086] In the next step of the reaction sequence disclosed in
Reaction Scheme 1, the 1-aryl or
1-heteroaryl-7-bromo-3,4-dihydronaphthalene derivatives of Formula
4 are reacted with dimethylformamide (DMF) in the presence of
tertiary-butyl lithium to provide the 1-aryl or
1-heteroaryl-3,4-dihydronaphthalene-7-aldehydes of Formula 5. The
aldehyde compounds of Formula 5 can also be obtained by first
converting the 7-bromo function of the compounds of Formula 4 into
a carboxylic acid ester function or carboxylic acid, to give the
1-aryl or 1-heteroaryl-3,4-dihydronaphthalene-7- carboxylic acid
esters (or acids, not shown in the scheme) of Formula 6. The
carboxylic acid methyl ester derivative is obtained, for example by
reaction with carbon monoxide and methanol in the presence of
palladium[2]bis(triphenylphoshine) chloride and
1,3-bis(diphenylphosphino)propane, as shown in the scheme. The
compounds of Formula 6 are reduced with a suitable reducing agent,
such as diisobutyl aluminum hydride (DiBAl-H) to provide the 1-aryl
or 1-heteroaryl-3,4-dihydronaphthalene-7-aldehydes of Formula
5.
[0087] The aldehydes of Formula 5 are subjected to a Horner Emmons
type reaction, in the presence of strong base such as n-butyl
lithium in hexane, with a 1-aryl or 1-heteroaryl
1-diethoxyphosphoryl-3,3-dimethoxyp- ropane derivative of Formula
7. An example of the phosphonate compound, which is used in the
preparation of several preferred compounds of the invention, is
ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate. Ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate is available in
accordance with the procedure of EPO Application No. 0 210 929
(published of Feb. 4, 1987, Shroot et al.) which is incorporated
herein by reference. In accordance with the Shroot et al. reference
the reagent ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate is made starting
with ethyl 4-bromobenzoate that is reacted with dimetyl acetal of
acryl aldehyde, the product is hydrogenated and subsequently
brominated (with N-bromo succinimide) and thereafter reacted with
triethylphosphite.
[0088] Other examples for the phoshonates of Formula 7 are ethyl
2-(diethoxyphosphoryl-3,3-dimethoxypropyl)pyridine-5-carboxylate,
ethyl
2-(diethoxyphosphoryl-3,3-dimethoxypropyl)pyridine-6-carboxylate,
ethyl
2-(diethoxyphosphoryl-3,3-dimethoxypropyl)thiophene-4-carboxylate,
ethyl
2-(diethoxyphosphoryl-3,3-dimethoxypropyl)thiophene-5-carboxylate,
ethyl
2-(diethoxyphosphoryl-3,3-dimethoxypropyl)furan-4-carboxylate,
ethyl
2-(diethoxyphosphoryl-3,3-dimethoxypropyl)furan-5-carboxylate.
These and analogous phosphonate reagents within the scope of
Formula 7 can be obtained by appropriate modification of the
procedure described in the Shroot et al. reference.
[0089] The product of the Horner Emmons reaction between the 1-aryl
or 1-heteroaryl-3,4-dihydronaphthalene-7-aldehydes of Formula 5 and
the 1-aryl or 1-heteroaryl
1-diethoxyphosphoryl-3,3-dimethoxypropane derivative of Formula 7
is a disubstituted ethene compound of Formula 8. Those skilled in
the art will readily understand that instead of a Horner Emmons
reaction, a Wittig reaction can also be employed, utilizing the
appropriate phosphonium derivative, to provide compounds of Formula
8.
[0090] The disubstituted ethene compounds of Formula 8 are
cyclized, for example by heating in a neutral solvent (such as
dischloromethane), in the presence of SnCl.sub.4 or other suitable
Friedel Crafts type catalyst, to form the "C ring" of the
3,4-dihydroanthracene derivatives of the invention, within the
scope of Formula 9. The compounds of Formula 9 can be converted
into further compounds of the invention by reaction well known to
the synthetic organic chemist, such as saponification,
esterification, amide formation and homologation. These reactions
were briefly described above, and the syntheses of these further
compounds of the invention is indicated in Reaction Scheme 1 as
conversion to "HOMOLOGS AND DERIVATIVES'. 8
[0091] Reaction Scheme 2 discloses the synthesis of compounds of
the invention where with reference to Formula 1 the X.sub.1 group
is --C(R.sub.1).sub.2--O--, --C(R.sub.1).sub.2--S--, or
--C(R.sub.1).sub.2--NR.sub.1-- where the Y group is phenyl,
naphthyl or heteroaryl and the R.sub.1 group is defined as in
connection with Formula 1. In other words, Reaction Scheme 2
discloses the preferred synthetic routes to compounds of the
invention which are benzo[1,2-g]-chrom-3-ene,
benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline
derivatives. As in Reaction Scheme 1 in this scheme also the
description is directed to a synthetic route for the preferred
examples in which the Y group is coupled to the 8 position of the
tricyclic condensed ring. In these preferred examples the
2-position of the tricyclic condensed ring bears tow (geminal)
methyl substituents. Nevertheless, those skilled in the art will
readily understand that the synthetic steps of Reaction Scheme 2
can be readily modified, within the skill of the art, to yield
other benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and
benzo[1,2-g]-1,2-dihydroquinoline compounds of the invention.
[0092] 6-Bromochroman-4-one, 6-bromothiochroman-4-one and
6-bromo-1,2,3,4-tetrahydroquinoline-4-one derivatives of Formula 10
serve as starting materials in the steps shown in Reaction Scheme
1. Specifically, 2,2-dimethyl-6-bromo-thiochroman-4-one can be
obtained from the reaction of thiophenol with 3,3-dimethylacrilic
acid, followed by cyclization of the resulting adduct, as is
described in detail in the "Specific Examples" section of this
application. 2,2-Dimethyl-6-bromochro- man-4-one can be obtained in
accordance with the procedure of Buckle et al. J. Med. Chem. 1990
33, 3028, which is expressly incorporated herein by reference.
2,2-Dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline can be obtained by
bromination with N-bromosuccinimide of
2,2-dimethyl-1,2,3,4-tetrahydroquinoline that is available in
accordance with the chemical literature (Helv. Chim. Acta (1990)
73, 1515-1573).
[0093] In accordance with Reaction Scheme 2, the
6-bromochroman-4-one, 6-bromothiochroman-4-one or
6-bromo-1,2,3,4-tetrahydroquinoline-4-one derivative of Formula 10
is reacted with a reagent of the formula R.sub.4--X.sub.2, where
X.sub.2 is halogen, preferably bromine, in the presence of strong
base, such as tertiary-butyl lithium or normal-butyl lithium.
R.sub.4 and X.sub.2 are defined as in connection with Reaction
Scheme 1. 4-aryl or 4-heteroaryl 6-bromochrom-3-ene, 4-aryl or
4-heteroaryl 6-bromothiochrom-3-ene or 4-aryl or 4-heteroaryl
6-bromo11,2,dihydroquinoline derivatives of Formula 11 are obtained
in this reaction after acid catalyzed dehydration of the tertiary
alcohol intermediate that is first formed in the reaction with
R.sub.4--X.sub.2. A Grignard reagent of the formula
R.sub.4--Mg--X.sub.2, or the metal salt, particularly the lithium
salt, of an aryl or heteroaryl compond of the forula R.sub.4--Li
can also be employed, to yield the 4-aryl or 4-heteroaryl
derivatives of Formula 11. The 4-aryl or 4-heteroaryl
6-bromochrom-3-ene, 4-aryl or 4-heteroaryl 6-bromothiochrom-3-ene
or 4-aryl or 4-heteroaryl 6-bromo-1,2,dihydroquinoline derivatives
of Formula 11 are converted into the aryl or heteroaryl substituted
benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and
benzo[1,2-g]-1,2-dihydroquinoline compounds of the invention in the
same, or substantially the same sequence of reactions, as is
described in Reaction Scheme 1. This sequence of reactions is shown
in Reaction Scheme 2, and specific examples for their application
are described in the "Specific Examples" section. The disubstituted
ethene compounds of Formula 13 are usually not isolated in a pure
form. Rather they are subjected to a cyclization reaction without
purification to provide the compounds of Formula 14, which can be
further converted into homologs and derivatives still within the
scope of the invention.
[0094] Compounds of the invention where with reference to Formula 1
the X.sub.1 group is --C(R.sub.1).sub.2-- can be made in analogy to
the synthetic steps outlined in Reaction Scheme 1, starting with
6-bromo-indan-1-one or from an appropriately subtituted derivative.
In these synthetic schemes 6-bromo-indan-1-one is used in analogy
to 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound
A) as a starting material. 6-bromo-3,3-dimethyl-indan-1-one is
available accordance with the chemical literature. (See Smith et
al. Org. Prep. Proced. Int., 1978, 10 123-131.)
[0095] Compounds of the invention where with reference to Formula
1, X.sub.1 is O, S, or NR.sub.1 can be made from the compounds
5-bromo-benzofuran-3-(2H) -one, 5-bromo-benzothiophene-3-(2H) -one
and 5-bromo-indol-3-(2H)-one, or from their appropriately
substituted derivatives, substantially in accordance with the
reaction steps set forth in Reaction Scheme 1. These are available
in accordance with the chemical literature. For
5-bromo-benzofuran-3(2H)-one see Ellingboe et al. J. Med. Chem.
(1992) 35 p1176, and for 5-bromo-benzothiophene-3(2H)-o- ne see
Pummerel et al. Chem. Ber. 42 (1909) 2279. 5-Bromo-indol-3-(2H) one
can be obtained from 5-bromo-indol-2,3-dione (Patrick et al. Tet.
Letts. (1984) 25 3099) by reduction with LiAlH.sub.4, followed by
oxidation with manganese dioxide (MnO.sub.2). 9
[0096] 5-bromo-benzofuran-3(2H)-one
[0097] 5-bromo-benzothiophene 3-(2H)-one
[0098] 5-bromo-indol-3-(2H)-one 10
[0099] Reaction Scheme 3 provides an example for the preparation of
compounds of the invention where with reference to Formula 1 Y is
--(CR.sub.3.dbd.CR.sub.3).sub.r-- and r is 2, although those
skilled in the art will be able to readily modify the steps
depicted in this reaction scheme to obtain additional compounds of
the invention where r is 1 or 3. The dimethyl acetal of ethyl
4-oxobutyrate is the starting material in accordance with this
scheme. The latter compound can be obtained in accordance with the
publication Smith et al. J. Am. Chem. Soc. 113 (6) 1991 pp
2071-2073. The dimethyl acetal of ethyl 4-oxobutyrate is brominated
with N-bromosuccinimide, and the resulting dimethyl acetal of
2-bromo-4-oxobutyrate is reacted with triethylphosphite to give the
dimethyl acetal of ethyl 2-diethylphosphoryl-2-oxo-butyrate. The
dimethyl acetal of ethyl 2-diethylphosphoryl-2-oxo-butyrate is
reacted in a Horner Emmons type reaction, in the presence of strong
base such as n-butyl lithium, with an aldehyde of Formula 15. In
Formula 15 R.sub.4 and X.sub.1 are defined as in connection with
Formula 1. Therefore, the aldehyde of Formula 15 can be an aldehyde
derivative of 1-aryl or 1-heteroaryl 1,2,3,4-tetrahydronaphthalene
or of a 4-aryl or 4-heteroaryl chrom-3-ene, 4-aryl, 4-heteroaryl
thiochrom-3-ene, or 4-aryl or 4-heteroaryl 1,2-dihydroquinoline.
More specific examples for the aldehydes which are used in this
reaction scheme are the aldehydes of Formula 5 disclosed in
connection with Reaction Scheme 1, and the aldehydes of Formula 12
disclosed in connection with Reaction Scheme 2. The product of the
Horner Emmons condensation reaction is a pentenoic acid derivative
of Formula 16, which is cyclized in the subsequent reaction step to
provide an ethyl carboxylate derivative of the aryl or heteroaryl
substituted 3,4-dihydroanthracene or aryl or heteroaryl substituted
benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and
benzo[1,2-g]-1,2-dihydroquinoline compounds shown in Formula 17.
The ethyl carboxylate function of the compounds of Formula 17 is
reduced with a suitable reducing agent, such as diisobutyl aluminum
hydride (DIBAl-H), to provide the aryl or heteroaryl substituted
3,4-dihydroanthracene aldehyde, aryl or heteroaryl substituted
benzo[1,2-g]-chrom-3-ene aldehyde, benzo[1,2-g]-thiochrom-3-ene and
benzo[1,2-g]-1,2-dihydroquinol- ine aldehyde compounds of Formula
18. The aldehydes of Formula 18 are then reacted in another Horner
Emmons reaction with ethyl-diethylphosphono-3-m- ethyl
2(E)butenoate which can be obtained in acordance with the
literature procedure of Corey et al J. Org. Chem. (1974) 39 p821.
The product of this last Horner Emmons reaction is the pentadienoic
acid derivative of Formula 19 which is within the scope of the
present invention. The compounds of Formula 19 can be converted
into further homologs and derivatives still within the scope of the
invention, as described above. 11
[0100] Reaction Scheme 4 discloses an alternative synthetic route
for preparing the compounds of the invention where, with reference
to Formula 1, the Y group is aryl or heteroaryl, as specifically
defined in connection with that formula. In accordance with this
scheme, the aldehyde derivative of a 1-aryl or 1-heteroaryl
1,2,3,4-tetrahydronaphtha- lene compound or of a 4-aryl or
4-heteroaryl chrom-3-ene, 4-aryl, 4-heteroaryl thiochrom-3-ene, or
4-aryl or 4-heteroaryl 1,2-dihydroquinoline compound of Formula 15
is reacted with the Wittig reagent
[2-(1,3-dioxolan-2-yl)ethyl)-triphenylphosphonium bromide in the
presence of strong base, such as n-butyl lithium. Specific examples
for the aldehydes which are used in this reaction scheme are the
aldehydes of Formula 5 disclosed in connection with Reaction Scheme
1, and the aldehydes of Formula 12 disclosed in connection with
Reaction Scheme 2. The Wittig reagent
[2-(1,3-dioxolan-2-yl)ethyl)triphenylphosphonium bromide is
commercially available from Aldrich Chemical Company Inc. The
product of the Wittig reaction is a disubstituted ethene compound
of Formula 20. The aryl or heteroaryl substituent designated "Y" is
introduced into this molecule in a Heck reaction, utilizing a
halogen substituted aryl or heteroaryl compound of the formula
X.sub.2--Y-A-B where X.sub.2 is halogen, preferably bromine or
iodine, A and B are defined as in connection with Formula 1, and Y
is aryl or heteroaryl as defined in Formula 1. Examples for the
reagents of formula X.sub.2--Y-A-B are ethyl 4-bromobenzoate, ethyl
2-bromopyridine-5-carboxylate, ethyl 2-bromopyridine-6-carboxylate,
ethyl 2-bromothiophene-4-carboxylate, ethyl
2-bromothiophene-5-carboxylate, ethyl 2-bromofuran-4-carboxylate,
and ethyl 2-bromofuran-5-carboxylate. The Heck reaction is well
known in the art, and is usually conducted in a basic solvent, such
as triethylamine, in the presence of a phosphine catalyst (such as
tris(2-methylphenyl)phosphine or tri-O-tolylphosphine) and in the
presence of palladium(II)acetate catalyst. The product of the Heck
reaction is a disubstituted ethene compound of Formula 21 which is
thereafter ring closed under Friedel Crafts like conditions (e. g.
in the presence of SnCl.sub.4) as in the analogous reactions
described in Reaction Schemes 1 and 2, to provide the compounds of
Formula 22. The compounds of Formula 22 are within the scope of the
invention, and can be converted into further compounds of the
invention by reactions well known in the art. This is designated
symbolically in the reaction scheme by showing conversion into
homologs and derivatives.
SPECIFIC EXAMPLES
[0101] 1-(Tol-4-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene
(Compound B)
[0102] To a mixture of Mg metal (650 mg, 27 mmol) in THF (20 mL)
was added 4-bromotoluene (5.3 g, 31 mmol) in THF (40 mL). The
mixture was stirred for 2 hours at ambient temperature and heated
to 70.degree. C. for 30 minutes. After cooling to ambient
temperature, 3,4-dihydro-4,4-dimethyl-7- -bromo-1(2H)-naphthalenone
(Compound A) (2.1 g, 8 mmol), in THF (5 mL) was added and heated to
70.degree. C. for 24 hours. The mixture was cooled to ambient
temperature and the reaction was quenched by addition of H.sub.2O.
The mixture was diluted with ether:ethylacetate (1:1, 100 mL) and
washed with saturated NH.sub.4Cl (15 mL), water (10 mL) and brine
(10 mL). The organic layer was dried with MgSO.sub.4. Solvent was
removed under reduced pressure to afford the crude product as an
oil. The product was dissolved in THF (20 mL). To this solution
p-toleune sulfonic acid (pTSA) (35 mg) was added and the mixture
was refluxed for 16 hours. The mixture was cooled to ambient
temperature, diluted with ethylacetate (160 mL), washed with 10%
NaHCO.sub.3 (20 mL), brine (20 mL), dried with MgSO.sub.4 and the
solvent wasremoved by evaporation. Purification by chromatography
on silica gel gave the title compound as a white solid.
[0103] .sup.1HNMR (CDCl.sub.3): .delta.1.33 (s, 6H), 2.34 (d, J=4.8
Hz, 2H), 2.42 (s, 3H), 6.00 (t, J=4.8 Hz, 1H), 7.17 (d, J=2.1 Hz,
1H), 7.20-7.30 (m, 5H), 7.34 (dd, J=2.1, 8.2 Hz, 1H).
[0104] 1-(Tol-4-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde
(Compound C)
[0105] To a cold (-78.degree. C.), stirred solution of
1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound
B 1 g, 3.2 mmol), in THF (17 mL) was added t-BuLi in pentane (1.7M
solution, 3 mL, 5.1 mmol). After 10 minutes dry dimethylformamide
(DMF) (600 mg, 8 mmol) was added and the dry-ice cooling was
replaced with ice-water bath. The mixture was gradually warmed to
ambient temperature and diluted with ethylacetate (150 mL), washed
with water (15 mL). The organic layer was dried with MgSO.sub.4 and
solvent was removed under reduced pressure. The crude material was
purified by silicagel chromatography to afford the title compound
as a white solid.
[0106] .sup.1HNMR (CDCl.sub.3): .delta.1.38 (s, 6H), 2.39 (d, J=4.9
Hz, 2H), 2.43 (s, 3H), 6.06 (t, J=4.9 Hz, 1H), 7.20-7.30 (m, 4H),
7.50-7.60 (m, 2H), 7.76 (dd, J=1.8, 8.0 Hz, 1H), 9.87 (s, 1H).
[0107] Ethyl
4-[1-(2,2-dimethoxyethyl-2-{1(tol-4-yl)3,4-dihydro-4,4-dimeth-
yl-naphthalen-7-yl}-(E)-ethenyl]-benzoate (Compound E)
[0108] To a cold (-78.degree. C.) solution of ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 350
mg, 0.9 mmol, available in accordance with EPO Application No. 0
210 929 published on Feb. 4, 1987), in THF (9 mL), was added n-BuLi
in hexane (1.6M solution, 0.7 mL, 1.1 mmol). The mixture was
stirred for 1.5 hours. To this solution
1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound C,
200 mg, 0.72 mmol), in THF (1 mL) was added and the mixture was
gradually warmed to ambient temperature (4 h). The reaction was
quenched by adding water (5 mL), and extracted with ethyl acetate
(3.times.25 mL). The organic layer was washed with brine (10 mL),
dried with MgSO.sub.4 and the solvent was removed by distillation.
The crude material was purified by silicagel chromatography to
afford the title compound as a colorless oil.
[0109] .sup.1HNMR (CDCl.sub.3): .delta.1.37 (s, 6H), 1.11 (t, J=7.1
Hz, 3H), 2.35 (d, J=4.6 Hz, 2H), 2.39 (s, 3H), 3.03 (d, J=5.9 Hz,
2H), 3.13 (s, 6H), 4.29 (t, J=5.9 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H),
5.98 (t, J=4.6 Hz, 1H), 6.73 (s, 1H), 7.13 (s, 1H), 7.20 (d, J=8.2
Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 7.40 (brs, 2H), 7.48 (d, J=8.3 Hz,
2H), 8.02 (d, J=8.3 Hz, 2H).
[0110] Ethyl
4-[1(tol-4yl)-3,4-dihydro-4,4-dimethyl-anthracen-8yl]-benzoat- e
(Compound 1)
[0111] To a cold (-50.degree. C.) solution of ethyl
4-[1-(2,2-dimethoxyethyl)-2-{1(tol-4-yl)3,4-dihydro-4,4-dimethyl-naphthal-
en-7-yl}-(E)-ethenyl]-benzoate (Compound E, 19 mg, 0.04 mmol), in
dichloromethane (3 mL), was added SnCl.sub.4 (2 mg in 0.1 mL of
dichloromethane). After 15 minutes the reaction was quenched by
adding water (2 mL), extracted with ether (60 mL). The organic
layer was washed with water (5 mL), brine (5 mL), dried with
MgSO.sub.4 and the solvent was removed by distillation. The product
was purified by silicagel chromatography to afford the title
compound as a white solid.
[0112] .sup.1HNMR (CDCl.sub.3): .delta.1.43 (t, J=7.1 Hz, 3H), 1.47
(s, 6H), 2.42 (d, J=4.9 Hz, 2H), 2.45 (s, 3H), 4.41 (q, J=7.1 Hz,
2H), 6.08 (t, J=4.9 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.34 d, J=8.0
Hz, 2H), 7.54 (s, 1H), 7.69 (dd, J=1.9, 8.4 Hz, 1H), 7.73 (d, J=8.4
Hz, 2H), 7.79 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.90 (brs, 1H), 8.11
(d, J=8.4 Hz, 2H).
[0113]
4-[1(Tol-4-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoic
acid (Compound 2)
[0114] To a degassed solution of ethyl
4-[1(tol-4-yl)3,4-dihydro-4,4-dimet- hyl-anthracen-8-yl]-benzoate
(Compound 1, 35 mg, 0.08 mmol), in THF (1.5. mL) and MeOH (1.5 mL)
was added LiOH (1M solution in water, 0.3. mL, 0.3 mmol). The
mixture was stirred at ambient temperature for 16 hours, diluted
with ether (60 mL). The mixture was acidified with 10% HCl to pH 4,
the product was isolated as an ether insoluble white solid.
[0115] .sup.1HNMR (DMSO-D.sub.6): .delta.1.11 (s, 6H), 2.38 (s,
3H), 2.39 (d, J=4.5 Hz, 2H), 6.07 (t, J=4.5 Hz, 1H), 7.25-7.33 (m,
4H), 7.51 (s, 1H), 7.84 (dd, J=1.6, 8.6 Hz, 1H), 7.90-8.05 (m, 6H),
8.15 (s, 1H).
[0116]
1-(5-Methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene
(Compound F)
[0117] To a cold (-78.degree. C.) solution of 2-methylthiophene
(800 mg, 8.1 mmol) in THF (10 mL) was added n-BuLi (1.6M solution
in hexane, 5 mL). The mixture was stirred for 1.5 hours and
transferred to a cold (-78.degree. C.) flask containing
3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-- naphthalenone (Compound A,
1.63 g, 6.5 mmol), in THF (15 mL). The mixture was gradually warmed
to 0.degree. C. The reaction mixture was diluted with
ether:ethylacetate (1:1, 80 mL), washed with water (10 mL), brine
(10 mL). dried with MgSO.sub.4 and the solvent was removed by
evaporation. The crude material was dissolved in dichloroethane (20
mL) and pTSA (40 mg) was added. The mixture was stirred at ambient
temperature for 16 hours and at 50.degree. C. for 4 hours. . The
reaction mixture was diluted with ether (150 mL), washed with
aqueous 10% NaHCO.sub.3 (10 mL), brine (10 mL) and dried with
MgSO.sub.4. Purification by chromatography on silica gel gave 1.35
g of the title compound as a white solid.
[0118] .sup.1HNMR (CDCl.sub.3): .delta.1.26 (s, 6H), 2.31 (d, J=4.9
Hz, 2H), 2.52 (s, 3H), 6.15 (t, J=4.9 Hz, 1H), 6.72 (d, J=3.3 Hz,
1H), 6.83 (d, J=3.3 Hz, 1H), 7.21 (d, J=8.3H, 1H), 7.34 (dd, J=2.0,
8.3 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H).
[0119]
1(5-Methyl-thien-2-yl)3,4-dihydro-4,4-diethyl-7-naphthaldehyde
(Compound G)
[0120] To a cold (-78.degree. C.) solution of
1-(5-methyl-thien-2-yl)-3,4--
dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound F, 1.35 g, 4.1
mmol), in THF (20 mL) was added t-BuLi in pentane (1.7M solution,
3.5 mL, 5.95 mmol). The reaction was stirred for 15 minutes. and
DMF (600 mg, 5.8 mmol) was added and dry-ice cooling was replaced
with ice-water bath. The mixture was stirred at ambient temperature
for 4 hours. The reaction mixture was diluted with ether (70 mL)
and washed with water (5 mL), brine (5 mL) and dried with
MgSO.sub.4. Solvent was removed by distillation. The product was
purified by silicagel chromatography to afford the title compound
as a colorless oil.
[0121] .sup.1HNMR (CDCl.sub.3): .delta.1.35 (s, 6H), 2.35 (d, J=4.8
Hz, 2H), 2.52 (s, 3H), 6.20 (t, J=4.8 Hz, 1H), 6.73 (d, J=3.5 Hz,
1H), 6.86 (d, J=3.5 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.77 (dd,
J=1.8, 7.9 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 9.93 (s, 1H).
[0122] Ethyl
4-[1(2,2-dimethoxyethyl)-2-{1-(5-methyl-thien-2-yl)3,4-dihydr-
o-4,4-dimethyl-naphthalen-7-yl}-(E)-ethen-1-yl]-benzoate (Compound
H)
[0123] To a cold (-78.degree. C.) solution of ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4
g, 3.6 mmol), in THF (20 mL) was added n-BuLi (1.6 M solution in
hexane, 2.5 ml, 4 mmol). The mixture was stirred for 20 minutes at
-78.degree. C. and 10 min. at -10.degree. C. The reaction mixture
was recooled to -78.degree. C. and
1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-napht- haldehyde
(Compound G, 650 mg, 2.3 mmol) in THF (4 mL) was added to it. The
mixture was stirred for 2 hours at -10.degree. C. and diluted with
ether (100 mL), washed with brine (10 mL) dried with MgSO.sub.4 and
the solvent was removed by distillation to to afford a cis and
trans (E and Z) isomeric mixture. Purification by chromatography on
silica gel of the crude material afforded the title compound as an
oil (.sup..about.90% purity).
[0124] .sup.1HNMR (CDCl.sub.3): .delta.1.33 (s, 6H), 1.41 (t, J=7.1
Hz, 3H), 2,32 (d, J=4.9 Hz, 2H), 2.49 (s, 3H), 3.06 (d, J=5.7 Hz,
2H), 3.16 (s, 6H), 4.32 (t, J=5.7 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H),
6.13 (t, J=4.9 Hz, 1H), 6.70 (d, J=3.5 Hz, 1H), 6.78 (s, 1H), 6.85
(d, J=3.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.43 (dd, J=1.7, 8.0 Hz,
1H), 7.50 (d, J=8.3 Hz, 3H), 8.02 (d, J=8.3 Hz, 2H).
[0125] Ethyl
4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-
-yl]-benzoate (Compound 3)
[0126] To a cold (-50.degree. C.) solution of ethyl
4-[1-(2,2-dimethoxyethyl)-2-{1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimeth-
yl-naphthalen-7-yl}-(E)-ethenyl]-benzoate (Compound H, 130 mg, 0.25
mmol), in dichloromethane (5 mL) was added SnCl.sub.4 (22 mg, in
0.1 mL dichloromethane). After 15 min. the reaction was quenched by
adding solid NaHCO.sub.3 (100 mg) followed by aqueous 10%
NaHCO.sub.3 (5 mL), and the resulting mixture was extracted with
ether (60 mL). The organic layer was washed with water (5 mL),
brine (5 mL) dried with MgSO.sub.4 and the solvent was removed by
distillation. The product was purified by silicagel chromatography
to afford the title compound as a white solid.
[0127] .sup.1HNMR (CDCl.sub.3): .delta.1.43 (t, J=7.1 Hz, 3H), 1.44
(s, 6H), 2.40 (d, J=4.8 Hz, 2H), 2.56 (s, 3H), 4.41 (q, J=7.1 Hz,
2H), 6.25 (t, J=4.8 Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.96 (d, J=3.4
Hz, 1H), 7.71 (dd, J=1.7, 8.4 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.78
(s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.95 (brs, 1), 7.99 (brs, 1H),
8.12 (d, J=8.4 Hz, 2H).
[0128]
4-[1(5-Methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-b-
enzoic acid (Compound 4)
[0129] To a stirred solution of ethyl
4-[1-(5-methyl-thien-2-yl)-3,4-dihyd-
ro-4,4-dimethyl-anthracen-8-yl]-benzoate (Compound 3, 33 mg, 0.07
mmol), in THF (2 mL), MeOH (2 mL), was added aqueous LiOH (1M
solution, 0.2 mL, 0.2 mmol). After 16 hours, water (2 mL) was added
to the reaction mixture, about 50% of the organic solvents were
removed by distillation, and the mixture was further diluted the
mixture with water (5 mL). The reaction mixture was washed with
ether (10 mL) and the aqueous layer was acidified to pH 4 and
extracted with ethyl acetate (3.times.20 m). The combined organic
layers were washed water (5 mL), brine (10 mL), dried with
MgSO.sub.4 and the solvent was removed by distillation. The product
was recrystallized from acetone to obtain the title compound as a
white solid.
[0130] .sup.1HNMR (CDCl.sub.3): .delta.1.44 (s, 6H), 2.40 (d, J=4.9
Hz, 2H), 2.56 (s, 3H), 6.24 (t, J=4.9 Hz, 1H), 6.79 (d, J=3.4 Hz,
1H), 6.96 (d, J=3.4 Hz, 1H), 7.23 (dd, J=1.7, 8.4 Hz, 1H), 7.79
(brs, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.96 (s,
1H), 8.01 (s, 1H), 8.18 (d, J=8.4 Hz, 2H).
[0131]
1-(6-Methyl-pyrid-3-yl)-3,4-dihydro-4,4-dimethyl-7-bromo-naphthalen-
e (Compound I)
[0132] To a cold (-78.degree. C.) solution of
6-methyl-3-bromopyridine (890 mg, 5.2 mmol) in THF (15 mL) was
added n-BuLi in hexane (1.6M solution, 3.5 mL, 5.6 mmol) and
stirred for 1 hour. This mixture was added to a flask containing
3,4-dihydro-4,4-dimethyl-7-bromo-1(2H) -naphthalenone (Compound A,
1.35 g, 5.4 mmol), in THF (5 mL) at -78.degree. C. The reaction
mixture was gradually warmed to ambient temperature and stirred for
16 hours. Thereafter it was diluted with ethyl acetate (100 mL),
washed with water (10 mL), brine (10 mL) and dried with MgSO.sub.4.
Solvent was removed by distillation, the crude material was
dissolved in toluene (25 mL) and pTSA (530 mg, 2.8 mmol) was added.
The mixture was heated at 90.degree. C. for 36 hours. Thereafter it
was diluted with ethyl acetate (100 mL), washed with 10%
NaHCO.sub.3 (2.times.10 mL), brine (10 mL), dried with MgSO.sub.4
and the solvent was removed by evaporation. The title compound was
obtained by recrystallization from ethyl acetate and hexane mixture
(1:9).
[0133] .sup.1HNMR (CDCl.sub.3): .delta.1.31 (s, 6H), 2.34 (d, J=4.7
Hz, 2H), 2.60 (s, 3H), 6.02 (t, J=4.7 Hz, 1H), 7.05 (d, J=2.1 Hz,
1H), 7.17 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.34 (dd,
J=2.1, 8.2 Hz, 1H), 7.51 (d, J=2.3, 8.3 Hz, 1H), 8.46 (d, J=2.3 Hz,
1H).
[0134]
Ethyl1-(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-7-naphthoate
(Compound J)
[0135] Carbon monoxide gas was bubbled for 5 minutes through a
mixture of
1-(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene
(Compound J, 250 mg, 0.75 mmol), Et.sub.3N (5 mL), MeOH (10 mL),
DMSO (10 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (70 mg, 0.1 mmol) and
1,3-bis(diphenylphophino)propane (206 mg, 0.5 mmol). The mixture
was heated to 50.degree. C. for 16 hours under a carbon monoxide
atmosphere (carbon monoxide balloon). Thereafter solvent was
distilled off, water (15 mL) was added, and the mixture was
extracted with ethyl acetate (3.times.40 mL). The combined organic
layers were washed with water (10 mL), brine (10 mL) dried with
MgSO.sub.4 and the solvent was removed by evaporation. The crude
material was purified by silicagel column chromatography to afford
the title compound as a white solid.
[0136] .sup.1HNMR (CDCl.sub.3): .delta.1.33 (s, 6H), 2.35 (d, J=4.9
Hz, 2H), 2.59 (s, 3H), 3.80 (s, 3H), 6.03 (t, J=4.9 Hz, 1H), 7.16
(d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.51 (dd, J=2.2, 8.0 Hz,
1H), 7.60 (d, J=1.8 Hz, 1H), 7.89 (dd, J=1.8, 8.0 Hz, 1H), 8.47 (d,
J=2.2 Hz, 1H).
[0137]
16(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-naphthaldehyde
(Compound K)
[0138] To a cold (-78.degree. C.) solution of methyl
1-(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-7-naphthoate
(Compound J, 200 mg, 0.65 mmol), in dichloromethane (4 mL) was
added DiBAl-H in dichloromethane (1M solution, 2 mL, 2 mmol). The
mixture was stirred for 2 hours, quenched with aq. KOH solution
(100 mg in 2 mL), and a gel precipitate formed. The mixture was
transferred to a seperatory funnel, and was extracted with ethyl
acetate (3.times.30 mL). The combined organic layers were washed
with brine (10 mL), dried with MgSO.sub.4, and the solvent was
removed by evaporation. The crude product was dissolved in
dichloromethane (10 mL), MnO.sub.2 (650 mg, 7.5 mmol) was added and
the mixture was stirred for 6 hours. The solid was filtered off,
and the solvent was removed to afford the title compound as a white
solid. 1HNMR (CDCl.sub.3): .delta.1.38 (s, 6H), 2.41 (d, J=4.7 Hz,
2H), 2.63 (s, 3H), 6.09 (t, J=4.7 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H),
7.44 (d, J=1.8 Hz, 1H), 7.51-7.59 (m, 3H), 7.77 (dd, J=1.8, 8.0 Hz,
1H), 8.49 (d, J=1.8 Hz, 1H), 9.86 (s, 1H).
[0139] Ethyl
4-[1-(6-methyl-pyrid-3-yl)-3,4-dihydro-4,4-dimethyl-anthracen-
-8-yl]-benzoate (Compound 5)
[0140] This compound is prepared in accordance with the procedure
described for the preparation of ethyl
4-[1(5-methyl-thien-2-yl)3,4-dihyd-
ro-4,4-dimethyl-anthracen-8-yl]-benzoate (Compound 3), from
1(2-methyl-pyrid-5-yl)3,4-dihydro-4,4-dimethyl-naphthaldehyde
(Compound K) by reaction with ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzo- ate (Compound D)
and proceeding through the intermediate ethyl
4-[1-(2,2-dimethoxyethyl)-2-{1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-naphtha-
len-7-yl}-(E)-ethen-1-yl]-benzoate which is cyclized by treatment
with SnCl.sub.4 in dichloromethane to give the title compoud.
[0141]
4-[1(6-methyl-pyrid-5-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]--
benzoic acid (Compound 6)
[0142] The title compound is obtained by saponification with LiOH
of ethyl
4-[1(tol-4-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate
(Compound 5) in accordance with the procedure described for the
preparation of
4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthrace-
n-8-yl]-benzoic acid (Compound 4).
[0143] 3-Methyl-3-(4-bromo-thiophenyl) butyric acid (Compound
L)
[0144] A mixture of 4-bromothiophenol (9.5 g, 50 mmol),
3,3-dimethylacrylic acid (5 g, 50 mmol) and piperidine were heated
(110.degree. C.) in a screw cap heavy walled tube covered with
teflon cap. The reaction mixture became a thick liquid after 30
minutes of heating. Heating was continued for 23 hours. Then the
mixture was cooled to ambient temperature, andsolved in ethyl
acetate (200 mL). The mixture was washed with 10% aq. HCl, water
(50 mL), brine (50 mL) and dried with MgSO.sub.4. Solvent was
removed and the crude product was recrystallized from hexane to
afford the title compound as a colorless solid.
[0145] .sup.1HNMR (CDCl.sub.3): .delta.1.42 (s, 6H), 2.55 (s, 2H),
7.43 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H).
[0146] 2,2-Dimethyl-6-bromo-thiochroman-4-one (Compound M)
[0147] To a solution of 3-methyl-3-(4-bromo-thiophenyl) butyric
acid (Compound L, 9.1 g, 33.4 mmol) in benzene (125 mL) was added
oxalyl chloride (7.4 g, 59 mmol). The mixture was stirred for 5
hours at ambient temperature, and thereafter washed with ice-cold
5% NaOH (100 mL), ice-cold water (2.times.50 mL) and brine (50 mL).
The organic layer was dried with MgSO.sub.4 and the solvent was
removed by distillation. The residual colorless oil was dissolved
in dichloromethane (50 mL), cooled to 0.degree. C. and SnCl.sub.4
(14.7 g, 57 mmol) was added. The mixture was stirred at ambient
temperature for 14 hours, and poured into ice. The mixture was
extracted with ethyl acetate, washed with 10% NaOH, water, brine,
dried with MgSO.sub.4 and the solvent was removed by distillation.
The crude material was purified by silicagel chromatography and
after standing at ambient temperature for overnight crystalline
product was collected by filtration.
[0148] .sup.1HNMR (CDCl.sub.3): .delta.1.46 (s, 6H), 2.87 (s, 2H),
7.12 (d, J=8.4 Hz, 2H), 7.50 (dd, J=2.2, 8.4 Hz, 1H), 8.22 (d,
J=2.2 Hz, 1H).
[0149] 2,2-Dimethyl-4(tol-4-yl)-6-bromo-thiochrom-3-ene (Compound
N)
[0150] To a cold (-78.degree. C.) solution of 4-bromotoluene (720
mg, 4.2 mmol) in THF (8 mL) was added t-BuLi in pentane (1.7M, 0.5
mL, 0.85 mmol). The mixture was warmed to ambient temperature over
30 minutes with stirring. This mixture was added to a flask
containing 2,2-dimethyl-6-bromo-thiochroman-4-one (Compound M, 140
mg, 0.4 mmol) and THF (2 mL). and stirred for 16 hours at ambient
temperature. The reaction was quenched by adding aq. NH.sub.4Cl,
and the resulting mixture was extracted with ethylacetate, washed
with brine, dried and the solvent was removed by evaporation. The
product was isolated by chromatography on silica gel. The material
was dissolved in dichloromethane (5 mL) and pTSA (5 mg) was added
and heated to 50.degree. C. for 3 hours. The misture was diluted
with ethylacetate (20 mL), washed with 10% NaHCO.sub.3 (5 mL),
brine (5 mL), dried with MgSO.sub.4 and the solvent was removed by
evaporation to afford the title compound as an oil.
[0151] .sup.1HNMR (CDCl.sub.3): .delta.1.46 (s, 6H), 2.40 (s, 3H),
5.84 (s, 1H), 7.12-7.29 (m, 7H).
[0152] 2,2-Dimethyl-4(tol-4-yl)-thiochrom-3-en-6-al (Compound
O)
[0153] To a cold (-78.degree. C.) solution of
2,2-dimethyl-4(tol-4-yl)-6-b- romo-thiochrom-3-ene (Compound N, 280
mg, 0.81 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M
solution, 0.66 mL). The mixture was gradually warmed to -10.degree.
C. over 25 min. and recooled to -78.degree. C. To this solution was
added DMF (80 mg, 1.1 mmol) and stirred at ambient temperature for
5 hours. The reaction was quenched by adding water (10 mL), ethyl
acetate (100 mL), and the organic layer was washed with brine (10
mL), dried and the solvent removed by distillation. The crude
material was used in the next reaction without further
purification.
[0154] Ethyl
4-[2,2-dimethyl-4-(tol-4-yl)-6,7-benzothiochrom-3-en-7-yl]ben-
zoate (Compound 7).
[0155] To a cold (-78.degree. C.) solution of ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 536
mg, 1.4 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M
solution, 1.2 mL) and stirred for 1 hour between -78.degree. C. and
-10.degree. C. The mixture was cooled to -78.degree. C. and
2,2-dimethyl-4(tol-4-yl)-thiochr- om-3-en-6-al (Compound O, as
obtained in the previously described reaction) in THF (1 mL) was
added to it. The reaction mixture was stirred at ambient
temperature for 1 hour and diluted with ethyl acetate (60 mL),
washed with brine (10 mL), dried and the solvent was removed by
evaporation. The crude material was purified by column
chromatography to afford the E and Z isomers as a mixture. The
mixture of E and Z isomers was dissolved in dichloromethane (4 mL)
and cooled to -78.degree. C. To the cold solution was added SnCl4
(110 mg, 0.42 mmol) in dichloromethane (1 mL). The reaction mixture
was stirred between -78.degree. C. and -30.degree. C. for 30
minutes and then quenched with ethanol (0.2 mL), diluted with ethyl
acetate (30 mL), washed with brine, dried and the solvent was
removed by distillation. The crude material was purified by column
chromatography to obtain the title compound as a white solid.
[0156] .sup.1HNMR (CDCl.sub.3): d 1.43 (t, J=7.2 Hz, 3H), 1.53 (s,
6H), 2.44 (s, 3H), 4.41 (q, J=7.2 Hz, 2H), 6.02 (s, 1H), 7.21-7.31
(m, 4H), 7.59 (s, 1H), 7.69-7.75 (m, 3H), 7.80 (d, J=8.5 Hz, 1H),
7.88 (s, 2H), 8.11 (d, J=8.3 HZ, 2H).
[0157]
4-[2,2-dimethyl-4-(tol-4-yl)-6,7-benzothiochrom-3-en-7-yl]benzoic
acid (Compound 8)
[0158] To an argon purged solution of ethyl
4-[2,2-dimethyl-4-(tol-4-yl)-6-
,7-benzothiochrom-3-en-7-yl]benzoate (Compound 7, 12 mg, 0.03
mmol), THF (2 mL) and MeOH (1 mL) was added LiOH in water (1M
solution, 0.2 mL) and purged (with argon) for 2 minutes. The
mixture was stirred for 16 hours at ambeint temperature. The
reaction mixture was acidified with 10% hydrochloric acid to pH 4,
extracted with ethyl acetate (35 mL), washed with brine, dried and
the solvent was removed by distillation. The title compound was
obtained as an off white solid.
[0159] .sup.1HNMR (Acetone-D6): d1.50 (s, 6H), 2.39 (s, 3H), 6.08
(s, 1H), 7.26 (s, 4H), 7.84-7.96 (m , 5H), 8.12 (d, J=8.3 Hz,
3H).
[0160] 2,2-Dimethyl-4(tol-4-yl)-6-bromo-chrom-3-ene (Compound
P)
[0161] To cold (-78.degree. C.) solution of 4-bromotoluene (1.71 g,
10 mmol) in THF (16 mL) was added t-BuLi in pentane (1.7M, 3 mL).
The mixture was warmed to ambient temperature and stirred for 15
minutes and then recooled to -78.degree. C. To this solution,
2,2-dimethyl-6-bromo-ch- roman-4-one (750 mg, 3 mmol) in THF (4 mL)
was added and stirred for 30 minutes.
2,2-Dimethyl-6-bromo-chroman-4-one is available in accordance with
the procedure of Bickle et al. J. Med. Chem. 1990 33 p3028. The
reaction was quenched with water (5 mL), extracted with ethyl
acetate (10 mL), washed with brine, dried and the solvent was
removed by evaporation. Chromatography of the crude mixture
afforded 2,2-dimethyl-4-tolyl-4-hydox- y-6-bromo-chroman an oil.
This product was dissolved in dichloromethane (25 mL), and pTSA (25
mg) was added and the mixture stirred for 12 hours. The mixture was
then diluted with ethyl acetate (125 mL), washed with 10%
NaHCO.sub.3 (10 mL), brine, dried and the solvent was removed by
evaporation to afford a the title compound as a yellow oil.
[0162] .sup.1HNMR (CDCl.sub.3): .delta.1.48 (s, 6H), 2.41 (s, 3H),
5.61 (s, 1H), 6.76 (d, J=8.3 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 7.22
(s, 4H), 7.26 (dd, J=2.4, 8.3 Hz, 1H).
[0163] 2,2-Dimethyl-4(tol4-yl)-chrom-3-en-6-al (Compound Q)
[0164] To a cold (-78.degree. C.) solution of
2,2-dimethyl-4(tol-4-yl)-6-b- romo-chrom-3-ene (Compound P, 480 mg,
1.45 mmol) in THF (10 mL), was added t-BuLi in pentane (1.7M
solution, 1.1 mL) and the mixture was stirred for 30 minutes. DMF
(200 mg, 2.9 mmol) was added, the mixture was warmed to ambient
temperature and stirred for 3 hours. The reaction was diluted with
ethyl acetate (150 mL), washed with brine (10 mL), dried and the
solvent was removed by evaporation. Purification by chromatography
on silica gel column gave the title compound as a colorless
oil.
[0165] .sup.1HNMR (CDCl.sub.3): .delta.1.54 (s, 6H), 2.41 (s, 3H),
5.66 (s, 1H), 6.98 (d, J=8.3 Hz, 1H), 7.24 (s, 4H), 7.57 (d, J=2.0
Hz, 1H), 7.71 (dd, J=2.0, 8.3 Hz, 1H), 9.77 (s, 1H).
[0166]
Ethyl-4-[2,2-dimethyl-4-(tol4-yl)-benzo[1,2-g]-chrom-3-en-7-yl]benz-
oate (Compound 9)
[0167] To a cold (-78.degree. C.) solution of ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4
g, 3.6 mmol) in THF (9 mL) was added n-BuLi in hexane (1.6 M
solution, 2.8 mL). The mixture was gradually warmed to ambient
temperature over 30 minutes and stirred for 5 minutes. To this
mixture was added 2,2-dimethyl-4(tol-4-yl)-chrom-3-en-6-al
(Compound Q, 260 mg, 0.93 mmol) in THF (1 mL) at ambient
temperature and the mixture was stirred for 5 hours. The reaction
mixture was diluted with ethyl acetate (100 mL) and washed with
brine (10 mL) dried and the solvent was removed by evaporation. The
residual material was subjected to flash chromatography on
silicagel to obtain the E and Z olefinic compounds, which were
dissolved in dichloromethane (5 mL) and cooled to -50.degree. C. A
solution of SnCl.sub.4 in dichloromethane (150 mg in 0.7 mL) was
added to the olefinic compounds. The reaction mixture was gradually
warmed to -10.degree. C. over 3hours and then quenched with
methanol and water. The reaction mixture was diluted with ethyl
acetate (100 mL). The organic layer was washed with brine and
dried. Solvent was removed under reduced pressure and the residue
purified by chromatography on silicagel to afford the title
compound as a white solid.
[0168] .sup.1HNMR (CDCl.sub.3): .delta.1.43 (t, J=7.1 Hz, 3H), 1.55
(s, 6H), 2.45 (s, 3H), 4.41 (q, J=7.1 Hz, 2H), 5.85 (s, 1H),
7.24-7.38 (m, 5H), 7.53 (s, 1H), 7.65-7.78 (m, 4H), 7.88 (s, 1H),
8.11 (d, J=8.5 Hz, 2H).
[0169]
4-[2,2-Dimethyl-4-(tol-4-yl)-benzo(1,2-g)-chrom-3-en-7yl]benzoic
acid (Compound 10)
[0170] By following the procedure employed for the preparation of
4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoic
acid (Compound 4), ethyl
4-[2,2-dimethyl-4-(tol-4-yl)-benzo(1,2-g)-chrom--
3-en-7-yl]benzoate (Compound 9, 10 mg, 0.02 mmol), was converted
into the title compound using LiOH in water (0.2 mL, 0.2 mmol). The
title compound was obtained as an off white solid.
[0171] .sup.1HNMR (Acetone-D6): d 1.52 (s, 6H), 2.41 (s, 3H), 5.96
(s, 1H), 7.27-7.38 (m, 4H), 7.60 (s, 1H), 7.78-7.86 (m, 3H), 7.90
(d, J=8.2 Hz, 2H), 8.10 (d, J=8.2 Hz, 2H), 8.11 (s, 1H).
[0172] 2,2-Dimethyl-4(5-methyl-thien-2-yl)-6-bromo-chrom-3-ene
(Compound R)
[0173] To a cold (-78.degree. C.) solution of 2-methylthiophene
(820 mg, 8.3 mmol) in THF (16 mL) was added n-BuLi in hexane (1.6M,
4.4 mL, 8.5 mmol). The mixture was warmed to ambient temperature
and stirred for 15 minutes. This solution was added to a flask
containing cold (-78.degree. C.) solution of
2,2-dimethyl-6-bromo-chroman-4-one (1.08 g, 4.2 mmol) in THF (4
mL). The mixture was stirred and allowed to gradually warm to
ambient temperature over 8 hours, and then stirred for an
additional 4 hours at ambient temperature. The mixture was diluted
with ethyl acetate (200 mL), washed with 10% HCl, brine (20 mL),
dried and the solvent was removed by evaporation. The product was
purified by chromatography on a silica gel column to afford the
title compound as a colorless oil.
[0174] 1HNMR (CDCl.sub.3): .delta.1.46 (s, 6H), 2.52 (s, 3H), 5.75
(s, 1H), 6.73 (brs, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.5 Hz,
1H), 7.26 (dd, J=2.5, 8.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H).
[0175] 2,2-Dimethyl-4(5-methyl-thien-2-yl)-chrom-3-en-6-al
(Compound S)
[0176] To a cold (-78.degree. C.) solution of
2,2-dimethyl-4(5-methyl-thie- n-2-yl)-6-bromo-chrom-3-ene (Compound
R, 1.2 g, 3.6 mmol) in THF (10 mL), was added t-BuLi in pentane
(1.7M solution, 2.3 mL). After 30 minutes, DMF (465 mg, 5 mmol) was
added and the mixture was allowed to warm to ambient temperature
and stirred for 3 hours. The mixture was diluted with ethyl acetate
(150 mL), washed with brine (10 mL), dried and the solvent was
removed by evaporation. Purification by chromatography on silica
gel column gave the title compound as a colorless oil.
[0177] .sup.1HNMR (CDCl.sub.3): .delta.1.51 (s,6H), 2.52 (s, 3H),
5.80 (s, 1H), 6.75 (d, J=2.7 Hz, 1H), 6.91 (d, J=2.7 Hz, 1H), 6.97
(d, J=8.3 Hz, 1H), 7.73 (dd, J=2.0, 8.3 Hz, 1H), 7.94 (d, J=2.0 Hz,
1H), 9.83 (s, 1H).
[0178]
Ethyl-4-[2,2-dimethyl-4-(5-methyl-thien-2-yl)-benzo[1.2-g]-chrom-3--
en-7-yl]benzoate (Compound 11)
[0179] To a cold (-78.degree. C.) solution of ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 690
mg, 1.75 mmol) in THF (8 mL) was added n-BuLi in hexane (1.6 M
solution, 1.1 mL). The mixture was gradually warmed to ambient
temperature over 30 min and stirred for 5 minutes. The mixture was
recooled to -78.degree. C. and
2,2-dimethyl-4(5-methyl-thien-2-yl)-chrom-3-en-6-al (Compound S,
300 mg, 1.1 mmol) in THF (1 mL) was added to the reaction mixture.
The mixture was stirred at ambient temperature for 2 hours. The
reaction mixture was diluted with ethyl acetate (100 mL) and washed
with brine (10 mL) dried and the solvent was removed by
evaporation. The material was subjected to flash chromatography on
silica gel to obtain the E and Z olefinic compounds, which were
dissolved in dichloromethane (5 mL) and cooled to -78.degree. C. A
solution of SnCl.sub.4 in dichloromethane (52 mg in 0.2 mL) was
added to the olefinic compounds. The resulting mixture was stirred
for 30 minutes, quenched with methanol, water and diluted with
ethyl acetate (100 mL). The organic layer was washed with brine and
dried. Solvent was removed under reduced pressure and purified by
silicagel chromatography to afford the title compound as a white
solid.
[0180] .sup.1HNMR (CDCl.sub.3): .delta.1.43 (t, J=7.1 Hz, 3H), 1.53
(s, 6H), 2.56 (s, 3H), 4.41 (q, J=7.1 Hz, 2H), 5.99 (s, 1H), 6.79
(d, J=3.5 Hz, 1H), 7.00 (d, J=3.5 Hz, 1H), 7.29 (s, 1H), 7.68 (dd,
J=1.8, 8.5 Hz, 1H), 7.72-7.79 (m, 3H), 7.93 (s, 1H), 7.97 (s, 1H),
8.14 (d, J=8.5 Hz, 2H).
[0181]
4-[2,2-Dimethyl-4-(5-methyl-thien-2-yl)-benzo[1,2-g]-chrom-3-en-7-y-
l]benzoic acid (Compound 12)
[0182] To a solution of
ethyl-4-[2,2-dimethyl-4-(5-methyl-thien-2-yl)-benz-
o[1,2-g]-chrom-3-en-7-yl]benzoate (Compound 11, 18 mg, 0.03 mmol)
in methanol (0.5 mL) and THF (1 mL), was added LiOH in water (1M
solution, 0.3 mL). The reaction mixture was stirred for 20 hours,
the solvent was removed under reduced pressure, the residue
dissolved in water (5 mL), washed with ether (10 mL) and the
aqueous layer was acidified to PH 5. The aqueous layer was
extracted with ethyl acetate (3.times.20 mL). The combined organic
layers were washed with brine, dried, and the solvent was removed
under reduced pressure to afford the title compound as a pale
yellow solid.
[0183] .sup.1HNMR (CH.sub.3COCH.sub.3): .delta.1.50 (s, 6H), 2.52
(s, 3H), 6.11 (s, 1H), 6.85 (brs, 1H), 7.07 (d, J=3.3 Hz, 1H), 7.31
(s, 1H), 7.80-7.90 (m, 2H), 7.91 (d, J=8.4, 2H), 8.01 (s, 1H), 8.12
(d, J=8.4 Hz, 2H), 8.19 (s, 1H).
[0184] 2,2-Dimethyl-4(2-methyl-thien-5-yl)-6-bromo-thiochrom-3-ene
(Compound T)
[0185] To a cold (-78.degree. C.) solution of 2-methylthiophene
(1.2 g, 12.2 mmol) in THF (8 mL) was added n-BuLi in hexane (1.6M,
8.5 mL). The mixture was warmed to ambient temperature over 30
minutes. with stirring. The mixture was recooled to -78.degree. C.
and a solution of 2,2-dimethyl-6-bromo-thiochroman-4-one (Compound
M, 1.4 g, 5.2 mmol) in THF (10 mL) was added. The mixture was
stirred for 16 hours at ambient temperature. Then the reaction
mixture was diluted with ether (125 mL), washed with water (10 mL),
brine (10 mL) dried and the solvent was removed by evaporation. The
product was seperated by column chromatography and was dissolved in
dichloromethane (5 mL). To this solution p-TSA (5 mg) was added and
the mixture was stirred at ambient temperature for 5 min. The
reaction was quenched with 10% NaHCO.sub.3 (3 mL), washed with
brine (5 mL), dried and the solvent was removed by distillation.
The residual crude material was purified by column chromatography
to obtain the title compound as a pale yellow oil.
[0186] .sup.1HNMR (CDCl.sub.3): d 1.44 (s, 6H), 2.51 (s, 3H), 6.00
(s, 1H), 6.72 (d, J=1.1 Hz, 1H), 6.79 (d, J=1.1 Hz, 1H), 7.23 (d,
J=8.2 Hz, 1H), 7.29 (dd, J=2.1, 8.2 Hz, 1H), 7.58 (d, J=2.1 Hz,
1H).
[0187] 2,2-Dimethyl-4(2-methyl-thien-5-yl)-thiochrom-3-en-6-al
(Compound U)
[0188] To a cold (-78.degree. C.) solution of
2,2-dimethyl-4(2-methyl-thie- n-5-yl)-6-bromo-thiochrom-3-ene
(Compound T, 430 mg, 1.2 mmol) in THF (12 mL) was added n-BuLi in
hexane (1.6 M solution, 1 mL). The mixture was gradually warmed to
ambient temperature over 1 hour and recooled to -78.degree. C. To
this solution was added DMF (220 mg, 3 mmol) and the mixture was
stirred at ambient temperature for 16 hours. The reaction was
quenched by adding water (10 mL) and ethy lacetate (100 mL). The
organic layer was washed with brine (10 mL), dried and the solvent
was removed by distillation to obtain the title compound as a pale
yellow oil.
[0189] .sup.1HNMR (CDCl.sub.3): d 1.47 (s, 6H), 2.51 (s, 3H), 6.03
(s, 1H), 6.72 (d, J=2.5 Hz, 1H), 6.80 (d, J=2.5 Hz, 1H), 7.49 (d,
J=8.1 Hz, 1H), 7.68 (dd, J=1.7, 8.1 Hz, 1H), 7.95 (d, J=1.7 Hz,
1H), 9.88 (s, 1H).
[0190] Ethyl
[0191]
4-[2,2-dimethyl-4-(2-methyl-thien-5-yl)-6,7-benzothiochrom-3-en-7-y-
l]ben zoate (Compound 13)
[0192] To a cold (-78.degree. C.) solution of ethyl
4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 500
mg, 1.29 mmol) in THF (2.5 mL) was added freshly prepared lithium
diisopropylamide in THF(1.5 mmol). The mixture was allowed to warm
to -5.degree. C. over a period of 1 hour and 40 minutes. The
reaction mixture was recooled to -78.degree. C. and
2,2-dimethyl-4(2-methyl-thien-- 5-yl)-thiochrom-3-en-6-al (Compound
U, 180 mg, 0.58 mmol) in THF (2 mL) was added. The reaction mixture
was gradually warmed to -10.degree. C. over 2 hours. Then the
reaction was quenched by adding water (5 mL) and ethyl acetate (70
mL). The organic layer was washed with brine (10 mL) dried and the
solvent was removed by distillation. The product E and Z isomers
were isolated by column chromatography. The required E (minor)
isomer (45 mg) was dissolved in dichloromethane (5 mL) and cooled
to -78.degree. C. To this solution SnCl.sub.4 (110 mg, 0.42 mmol)
in dichloromethane (1 mL) was added dropwise, the reaction mixture
was gradually warmed to -30.degree. C. over 30 min. The reaction
was quenched by adding ethanol (0.5 mL), water (5 mL) and ethyl
acetate (75 mL). The organic layer was washed with brine (10 mL),
dried and the solvent was removed by distillation. The title
compound was isolated as a white solid after column
chromatography.
[0193] .sup.1HNMR (CDCl.sub.3) : d 1.43 (t, J=7.1 Hz, 3H), 1.55 (s,
6H), 2.55 (s, 3H), 4.42 (q, J=7.1 HZ, 2H), 6.19 (s, 1H), 6.75 (d,
J=1.9 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 7.70-7.85 (m, 4H), 7.87 (s,
1H), 7.97 (s, 1H), 8.00 (s, 1H), 8.12 (d, J=8.4 Hz, 2H).
[0194]
4-[2,2-Dimethyl-4-(2-methyl-thien-5-yl)-benzo(1,2-g)-thiochrom-3-en-
-7-yl]benzoic acid (Compound 14)
[0195] To a degassed solution of ethyl
4-[2,2-dimethyl-4-(2-methyl-thien-5-
-yl)-benzo(1,2-g)-thiochrom-3-en-7-yl]benzoate (Compound 13, 28 mg,
0.06 mmol), in THF (2 mL) and MeOH (1 mL) was added LiOH (1M
solution in water, 0.2 mL) and the mixture was stirred for 16
hours. The reaction was acidified to pH 4 and extracted with ethyl
acetate (50 mL). The organic layer was washed with brine, dried and
the solvent was removed to afford the title compound as a pale
yellow solid.
[0196] .sup.1HNMR (CDCl.sub.1) : d 1.52 (s, 6H), 2.55 (s, 3H), 6.19
(s, 1H), 6.74 (d, J=1.9 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 7.71-7.85
(m, 4H), 7.88 (s, 1H), 7.97 (s, 1H), 8.00 (s, 1H), 8.12 (d, J=8.4
Hz, 2H).
* * * * *